Exome sequencing greatly expedites the progressive research of Mendelian diseases

Abstract

The advent of whole-exome sequencing (WES) has facilitated the discovery of rare structure and functional genetic variants. Combining exome sequencing with linkage studies is one of the most efficient strategies in searching disease genes for Mendelian diseases. WES has achieved great success in the past three years for Mendelian disease genetics and has identified over 150 new Mendelian disease genes. We illustrate the workflow of exome capture and sequencing to highlight the advantages of WES. We also indicate the progress and limitations of WES that can potentially result in failure to identify disease-causing mutations in part of patients. With an affordable cost, WES is expected to become the most commonly used tool for Mendelian disease gene identification. The variants detected cumulatively from previous WES studies will be widely used in future clinical services.

Keywords

genetics / whole-exome sequencing / Mendelian disease / disease gene

Introduction

Monogenic disease (also called Mendelian disease) caused by a single gene variant conforms to the laws of Mendelian inheritance. Over 6000 Mendelian diseases have been identified according to the statistics of Online Mendelian Inheritance in Man (OMIM); however, the pathogenic genes of about half of these diseases remain unknown (http://www.ncbi.nlm.nih.gov/omim, 2011).

The next-generation sequencing (NGS) technology introduced in 2005 is a high-profile tool with advantages in detecting genetic variations ranging from single nucleotides to larger structural rearrangements. Whole-exome sequencing (WES) can be used to perform NGS of exon-enriched samples and to identify protein-coding mutations, including missense, nonsense, splice site, and small deletion/insertion mutations. Using WES in Mendelian disorders only needs a small number of individuals with family. The application of WES is a revolutionary progress in Mendelian disease research [1,2].

Traditional approaches of disease gene identification

Different strategies, including candidate gene study, and combined linkage study and positional cloning, have been applied in identifying causative genes for over several decades [3]. These previous approaches need the foundation of a set of disease genes identified by bioinformatic tools, such as gene functional similarity search tool (GFSST)and CANDID, a flexible method for prioritizing candidate genes for complex human traits [4,5]. However, most rare Mendelian diseases remain unknown, and a few candidate genes could be validated in affected families. The next to appear was the linkage study, which developed as the main tool to elucidate the genetics of Mendelian disorders. According to the principle with a perfect segregation pattern of the causal variant with the disorder in consanguineous families. Combining linkage study with follow-up positional cloning has found one-half to one-third (~3000) of genes underlying Mendelian disorders [6]. However, these conventional strategies are not efficient in detecting extremely rare Mendelian genetic disorders or de novo genes in sporadic cases.

WES technology

With the recent developments in NGS technologies and commercial whole exome-enrichment kits [7], exome sequencing has been widely used in identifying mutations or genes for Mendelian diseases [8]. Compared with traditional approaches and genome-wide association study, this technology only sequences approximately 1% of the genome that is in the coding-protein area and forms modest bioinformatic data, whereas almost 85% of mutations for Mendelian diseases are in gene-coding regions [3]. Moreover, this technology can reduce the time and cost of sequencing and detect the causative mutations directly. With this technology, researchers can use small family samples to find disease-causing variants. This technology also overcomes the large barriers in researching rare Mendelian diseases and opens a new phase in the study of Mendelian diseases. Using targeted capture and massively parallel sequencing to deal with the exomes of 12 humans (eight HapMap individuals and four individuals with Freeman-Sheldon syndrome), researchers found exome sequencing to identify candidate genes for Mendelian diseases with an unrelated, small size of affected individuals in 2009 [1].

Currently available NGS technologies, such as IlluminaHiSeq™, Life Technologies™ SOLiD4™, and Roche 454 GS FLX, generate hundreds of millions of short sequence reads with an average length of 50 bp to 125 bp. Fragment sequencing has higher sequencing error rates than Sanger sequencing; thus, further validation using Sanger sequencing is essential [9]. The weaknesses of these technologies are solved with the arrival of third-generation sequencing technologies; they can omit amplification steps in emulsion and bridge processes, and avoid errors in the polymerase-mediated amplification and “dephasing” stages. Helicos Biosciences and Pacific Biosciences revolutionized and provided this sequencing technology [10,11]. All neotype sequencers can generate considerable data from detective bases. Statistical strategies committed to measure the average frequency of de novo variants are used and compared with the common variation found in dbSNP. With the application of the Bonferroni correction, the true variants would be distinguished through the yielded threshold [2].

Typical samples used for WES

Previous disease-searching methods always need large families to be explored and ignore small families or sporadic cases. WES appears as a personalized medicine strategy for searching disease-causing genes. Consequently, the genetic defects of small Mendelian families or single sporadic case can now be determined [12].

Design in terms of certain mode of inheritance

Three strategies, namely, overlap-based, linkage-based, and de novo-based strategies, for sequence sample selection are commonly summed up according to the information of pedigrees [13]. The overlap-based strategy is mainly used in the absence of genetic heterogeneity. The most potential causative gene can be rapidly decreased to a small number by sequencing in multiple unrelated patients with the same phenotype. The linkage-based strategy is appropriate for the collection of a large family with prominent phenotype. Distantly related individuals share only a small fraction of the genome. Nonphenotypic individuals within the family are also added for exome sequencing. We can rapidly locate the causative variant in the linkage region. The de novo-based strategy is a highly effective approach for searching causative genes in parent-child trios. This strategy is applicable for sporadic patients. We sequenced the unaffected parents and affected child to detect de novo mutations that are responsible for rare Mendelian disorders [12].

Exome capture pipeline

The three main steps of exome sequencing are exome enrichment, DNA high-throughput sequencing, and biological interpretation. Exome enrichment is the basis for exome sequencing. Genomic DNA is randomly sheared and used to construct a shotgun library. The exome regions are enriched by hybridization capture (using oligonucleotide probes to hybridize the fragments of interest). The noncoding DNA sequences are then removed. Agilent, Nimblegen, Illumina, and other companies offer exome-enrichment kits for exome capture [14,15]. Exome-enrichment kits not only aim at protein coding regions and splice sites but also focus on the sequences of the pair end of exome, such as exon-flanking regions and predicted miRNA fragments. High-throughput methods can isolate exons more effectively than traditional methods.

Typical analysis pipeline

After sample preparation and sequencing, 20 000 and 50 000 variants are identified per sequenced exome. The disease-causing variants should be focused on the nonsynonymous (NS) variants, splice acceptor-site or donor-site mutations, and insertions/deletions. Variants are absent from the most known variant databases, such as dbSNP, the 1000 Genomes Project, other published studies, or in-house databases. This step can greatly reduce the number of potential candidate mutations by 90% to 95% [16]. We then selected the variants conformed to the geno-phenotype cosegregation. Further reduced candidate variants can be predicted by ANNOVAR or SIFT. Finally, the predicted damaging variants can be sequenced by the traditional Sanger sequencing to confirm the real causative variant. The detailed analytic flowchart is shown in Fig. 1.

Application of WES in Mendelian diseases

A rapid genetic explorative era has emerged since the release of the first draft of the human genome sequence in 2001. The human genome sequence was completed in 2003. In the following year, next-generation technologies were introduced and a theoretical system was accomplished. The first NGS platform was released in the market in 2005, which laid the foundation for commercial applications. Ng et al. performed WES in Miller syndrome in 2010 [2]. They were the first to apply exome sequencing successfully to a rare Mendelian disease. Since then, exome sequencing has been widely used to identify mutations for dominant or recessive diseases and has made great progress.

In January 2013, approximately 150 types of Mendelian disorders have been studied by WES, with coverage of each physiological system (Table 1).

Development of technical research

The extensive commercial use of high-throughput sequencing exome-enrichment kits has intensively decreased the cost of WES and has achieved adequate sequencing depth. Thus, various biological functions and clinical translational research have been respectively determined and conducted using WES. In 2009, Choi et al. [167] reported a case with clinical manifestations of dehydration and evaluation of failure to thrive. Such case was diagnosed as Bartter syndrome, but some other diseases could not be excluded. The missense variant in SLC26A3 was identified through exome sequencing analysis. Strom et al. [153] performed WES in nine putative Stargardt disease probands and identified seven disease-causing variants across four retinal or macular dystrophy genes. This study was used as basis to make a definite diagnosis in six previously uncharacterized individuals. Joubert syndrome is clinically featured with the “molar tooth sign” on brain images, accompanied by neurological symptoms, including episodic hyperpnea, a heterogeneous disease that is caused by 17 genes. Tsurusaki [168] applied WES to five JSRD pedigrees and found the causative mutations in all families. These results support the advantages of using WEG in molecular diagnosis.

The disease-causing variants and genes identified by WES can help researchers discover new drug targets. Identifying the genetic bases and mechanisms of Mendelian disorders is necessary to realize accurate diagnosis and treatment of these diseases based on etiology. Thus, medical genomics has become a reality with exome sequencing [169].

Technical limitation

Many causative genes for Mendelian diseases have been detected by exome sequencing. However, some limitations impede the complete explanation of genetic bases. First, although WES has achieved a great progress in the diagnosis of monogenetic diseases, the human genome is highly variable, and the rare variants outside coding exons can also confer disease. Approximately 85% of such diseases are caused by the coding exons and>15% lie outside the exons, including simple nucleotide variations (SNVs) and copy-number variants (CNVs), in the noncoding, conserved, or regulatory regions. The latter data cannot be assayed with the use of WES [170]. Second, the shared databases, including dbSNP or HapMap, cannot effectively exclude common and irrelative variants. Exome sequencing usually generates>10 000 variants per sample; thus, classifying variants with different frequencies and refining candidate genes in a small data set are the challenges in diagnosing partial disorders [171], especially extremely rare disorders. Third, some GC-rich sequences can lead to uneven coverage and incomplete capture because of the inherent defect of WES technology. Studies have revealed that 80% to 90% of the targeted regions are covered by more than 10 × and can also leave 4 Mb to 8 Mb (or 1000 to 2000 genes) without sufficient coverage for variant detection [172]. Furthermore, studies are mainly restricted by the effectiveness of variant filters and by the segmental duplications that biologically exist in the reference sequence, which can prevent accurate reading. Statistical metrics are necessary to distinguish false positives from true positives [169].

Conclusions and future directions

The sequencing of individual exome generally contains 20 000 to 25 000 coding variants, of which 9000 to 11 000 variants are NS, which can potentially consist of the genetic factors that cause a Mendelian disease [170]. An individual with phenotypic manifestations would likely carry 40 to 100 deleterious variants simultaneously. Several variation patterns and constituted haplotypes are belived to exist in individual human genomes that are transferred in “father-to-son” pedigree. Although several diploid individual human genomes have been sequenced, the haplotypes in these genomes remain unclear [173]. All the variants in affected individuals must be detected, and the haplotype project in human must be continually improved. However, mutant gene varies among different individuals affected with Mendelian diseases. Not only one gene affects the disease onset. However, the mechanism by which different genes trigger the same disease remains unknown. The functional influences of the responsible genes should be determined. The functions of approximately 20 000 genes have not been assigned, and the gene interaction needs to be elucidated [170].

The success rate of using the present technology to explore the genes responsible for Mendelian disorders ranges from 60% to 80%, which could be constantly improved by an adequate depth of sequencing. With the reduction in sequencing expense, whole-genome sequencing can be used to search all abnormal sequence information and reveal their correlation. This technology is automatable and removes the capture step, thereby reducing the false-positive rate and resulting in the detection of approximately 3.5 million variants per genome, including all genomic variation (SNVs and CNVs). This technology is especially suitable for complex trait gene identification and sporadic cases caused by de novo SNVs or CNVs [174].

The components of a medically actionable variant have yet to be identified. Guidelines for the clinical interpretation of exome sequencing are beginning to be established. WES is expected to become the most commonly used tool for searching the causative genes in Mendelian disorders. More variants would be detected in the future, and diagnostic molecular chip would be on market for clinical service applications.

Compliance with ethics guidelines

Xuejun Zhang declares no conflict of interest. This manuscript is a review article and does not involve a research protocol that requires approval by relevant institutional review board or ethics committee.

References

[1] Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE, Bamshad M, Nickerson DA, Shendure J. Targeted capture and massively parallel sequencing of 12 human exomes. Nature2009; 461(7261): 272-276

[2] Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet2010; 42(1): 30-35

[3] Botstein D, Risch N. Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease. Nat Genet2003; 33(3s Suppl): 228-237

[4] Zhang P, Zhang J, Sheng H, Russo JJ, Osborne B, Buetow K. Gene functional similarity search tool (GFSST). BMC Bioinformatics2006; 7(1): 135.

[5] Hutz JE, Kraja AT, McLeod HL, Province MA. CANDID: a flexible method for prioritizing candidate genes for complex human traits. Genet Epidemiol2008; 32(8): 779-790

[6] McKusick VA. Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet2007; 80(4): 588-604

[7] Clark MJ, Chen R, Lam HY, Karczewski KJ, Chen R, Euskirchen G, Butte AJ, Snyder M. Performance comparison of exome DNA sequencing technologies. Nat Biotechnol2011; 29(10): 908-914

[8] Teer JK, Mullikin JC. Exome sequencing: the sweet spot before whole genomes. Hum Mol Genet2010; 19(R2): R145-R151

[9] Ku CS, Wu M, Cooper DN, Naidoo N, Pawitan Y, Pang B, Iacopetta B, Soong R. Exome versus transcriptome sequencing in identifying coding region variants. Expert Rev Mol Diagn2012; 12(3): 241-251

[10] Bowers J, Mitchell J, Beer E, Buzby PR, Causey M, Efcavitch JW, Jarosz M, Krzymanska-Olejnik E, Kung L, Lipson D, Lowman GM, Marappan S, McInerney P, Platt A, Roy A, Siddiqi SM, Steinmann K, Thompson JF. Virtual terminator nucleotides for next-generation DNA sequencing. Nat Methods2009; 6(8): 593-595

[11] Eid J, Fehr A, Gray J, Luong K, Lyle J, Otto G, Peluso P, Rank D, Baybayan P, Bettman B, Bibillo A, Bjornson K, Chaudhuri B, Christians F, Cicero R, Clark S, Dalal R, Dewinter A, Dixon J, Foquet M, Gaertner A, Hardenbol P, Heiner C, Hester K, Holden D, Kearns G, Kong X, Kuse R, Lacroix Y, Lin S, Lundquist P, Ma C, Marks P, Maxham M, Murphy D, Park I, Pham T, Phillips M, Roy J, Sebra R, Shen G, Sorenson J, Tomaney A, Travers K, Trulson M, Vieceli J, Wegener J, Wu D, Yang A, Zaccarin D, Zhao P, Zhong F, Korlach J, Turner S. Real-time DNA sequencing from single polymerase molecules. Science2009; 323(5910): 133-138

[12] Gilissen C, Hoischen A, Brunner HG, Veltman JA. Disease gene identification strategies for exome sequencing. Eur J Hum Genet2012; 20(5): 490-497

[13] Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet2011; 12(11): 745-755

[14] Kahvejian A, Quackenbush J, Thompson JF. What would you do if you could sequence everything? Nat Biotechnol2008; 26(10): 1125-1133

[15] Gnirke A, Melnikov A, Maguire J, Rogov P, LeProust EM, Brockman W, Fennell T, Giannoukos G, Fisher S, Russ C, Gabriel S, Jaffe DB, Lander ES, Nusbaum C. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol2009; 27(2): 182-189

[16] International HapMap 3 Consortium; Altshuler DM, Gibbs RA, Peltonen L, Altshuler DM, Gibbs RA, Peltonen L, Dermitzakis E, Schaffner SF, Yu F, Peltonen L, Dermitzakis E, Bonnen PE, Altshuler DM, Gibbs RA, de Bakker PI, Deloukas P, Gabriel SB, Gwilliam R, Hunt S, Inouye M, Jia X, Palotie A, Parkin M, Whittaker P, Yu F, Chang K, Hawes A, Lewis LR, Ren Y, Wheeler D, Gibbs RA, Muzny DM, Barnes C, Darvishi K, Hurles M, Korn JM, Kristiansson K, Lee C, McCarrol SA, Nemesh J, Dermitzakis E, Keinan A, Montgomery SB, Pollack S, Price AL, Soranzo N, Bonnen PE, Gibbs RA, Gonzaga-Jauregui C, Keinan A, Price AL, Yu F, Anttila V, Brodeur W, Daly MJ, Leslie S, McVean G, Moutsianas L, Nguyen H, Schaffner SF, Zhang Q, Ghori MJ, McGinnis R, McLaren W, Pollack S, Price AL, Schaffner SF, Takeuchi F, Grossman SR, Shlyakhter I, Hostetter EB, Sabeti PC, Adebamowo CA, Foster MW, Gordon DR, Licinio J, Manca MC, Marshall PA, Matsuda I, Ngare D, Wang VO, Reddy D, Rotimi CN, Royal CD, Sharp RR, Zeng C, Brooks LD, McEwen JE. Integrating common and rare genetic variation in diverse human populations. Nature2010; 467(7311): 52-58

[17] Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet2010; 42(9): 790-793

[18] Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M, Gronka S, Wuu J, Ding J, McCluskey L, Martinez-Lage M, Falcone D, Hernandez DG, Arepalli S, Chong S, Schymick JC, Rothstein J, Landi F, Wang YD, Calvo A, Mora G, Sabatelli M, Monsurrò MR, Battistini S, Salvi F, Spataro R, Sola P, Borghero G, Galassi G, Scholz SW, Taylor JP, Restagno G, Chiò A, Traynor BJ; Collaborators: Giannini F, Ricci C, Moglia C, Ossola I, Canosa A, Gallo S, Tedeschi G, Sola P, Bartolomei I, Marinou K, Papetti L, Conte A, Luigetti M, La Bella V, Paladino P, Caponnetto C, Volanti P, Marrosu MG, Murru MR. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron2010; 68(5): 857-864

[19] Wang JL, Yang X, Xia K, Hu ZM, Weng L, Jin X, Jiang H, Zhang P, Shen L, Guo JF, Li N, Li YR, Lei LF, Zhou J, Du J, Zhou YF, Pan Q, Wang J, Wang J, Li RQ, Tang BS. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain2010; 133(Pt 12): 3510-3518

[20] Sobreira NL, Cirulli ET, Avramopoulos D, Wohler E, Oswald GL, Stevens EL, Ge D, Shianna KV, Smith JP, Maia JM, Gumbs CE, Pevsner J, Thomas G, Valle D, Hoover-Fong JE, Goldstein DB. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet2010; 6(6): e1000991

[21] Johnson JO, Gibbs JR, Van Maldergem L, Houlden H, Singleton AB. Exome sequencing in Brown-Vialetto-van Laere syndrome. Am J Hum Genet2010; 87(4): 567-569, author reply 569-570

[22] Lalonde E, Albrecht S, Ha KC, Jacob K, Bolduc N, Polychronakos C, Dechelotte P, Majewski J, Jabado N. Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing. Hum Mutat2010; 31(8): 918-923

[23] Otto EA, Hurd TW, Airik R, Chaki M, Zhou W, Stoetzel C, Patil SB, Levy S, Ghosh AK, Murga-Zamalloa CA, van Reeuwijk J, Letteboer SJ, Sang L, Giles RH, Liu Q, Coene KL, Estrada-Cuzcano A, Collin RW, McLaughlin HM, Held S, Kasanuki JM, Ramaswami G, Conte J, Lopez I, Washburn J, Macdonald J, Hu J, Yamashita Y, Maher ER, Guay-Woodford LM, Neumann HP, Obermüller N, Koenekoop RK, Bergmann C, Bei X, Lewis RA, Katsanis N, Lopes V, Williams DS, Lyons RH, Dang CV, Brito DA, Dias MB, Zhang X, Cavalcoli JD, Nürnberg G, Nürnberg P, Pierce EA, Jackson PK, Antignac C, Saunier S, Roepman R, Dollfus H, Khanna H, Hildebrandt F. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet2010; 42(10): 840-850

[24] Anastasio N, Ben-Omran T, Teebi A, Ha KC, Lalonde E, Ali R, Almureikhi M, Der Kaloustian VM, Liu J, Rosenblatt DS, Majewski J, Jerome-Majewska LA. Mutations in SCARF2 are responsible for Van Den Ende-Gupta syndrome. Am J Hum Genet2010; 87(4): 553-559

[25] Byun M, Abhyankar A, Lelarge V, Plancoulaine S, Palanduz A, Telhan L, Boisson B, Picard C, Dewell S, Zhao C, Jouanguy E, Feske S, Abel L, Casanova JL. Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J Exp Med2010; 207(11): 2307-2312

[26] Bolze A, Byun M, McDonald D, Morgan NV, Abhyankar A, Premkumar L, Puel A, Bacon CM, Rieux-Laucat F, Pang K, Britland A, Abel L, Cant A, Maher ER, Riedl SJ, Hambleton S, Casanova JL. Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet2010; 87(6): 873-881

[27] Walsh T, Shahin H, Elkan-Miller T, Lee MK, Thornton AM, Roeb W, Abu Rayyan A, Loulus S, Avraham KB, King MC, Kanaan M. Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82. Am J Hum Genet2010; 87(1): 90-94

[28] Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med2010; 363(23): 2220-2227

[29] Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King MC. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am J Hum Genet2010; 87(2): 282-288

[30] Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, Uziel G, Lamantea E, Invernizzi F, Poulton J, Rolinski B, Iuso A, Biskup S, Schmidt T, Mewes HW, Wittig I, Meitinger T, Zeviani M, Prokisch H. Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet2010; 42(12): 1131-1134

[31] Krawitz PM, Schweiger MR, Rödelsperger C, Marcelis C, Kölsch U, Meisel C, Stephani F, Kinoshita T, Murakami Y, Bauer S, Isau M, Fischer A, Dahl A, Kerick M, Hecht J, Köhler S, Jäger M, Grünhagen J, de Condor BJ, Doelken S, Brunner HG, Meinecke P, Passarge E, Thompson MD, Cole DE, Horn D, Roscioli T, Mundlos S, Robinson PN. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nat Genet2010; 42(10): 827-829

[32] Gilissen C, Arts HH, Hoischen A, Spruijt L, Mans DA, Arts P, van Lier B, Steehouwer M, van Reeuwijk J, Kant SG, Roepman R, Knoers NV, Veltman JA, Brunner HG. Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am J Hum Genet2010; 87(3): 418-423 doi:10.1016/j.ajhg.2010.08.004

[33] Bilgüvar K, Oztürk AK, Louvi A, Kwan KY, Choi M, Tatli B, Yalnizoğlu D, Tüysüz B, Cağlayan AO, Gökben S, Kaymakçalan H, Barak T, Bakircioğlu M, Yasuno K, Ho W, Sanders S, Zhu Y, Yilmaz S, Dinçer A, Johnson MH, Bronen RA, Koçer N, Per H, Mane S, Pamir MN, Yalçinkaya C, Kumandaş S, Topçu M, Ozmen M, Sestan N, Lifton RP, State MW, Günel M. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature2010; 467(7312): 207-210

[34] Sirmaci A, Walsh T, Akay H, Spiliopoulos M, Sakalar YB, Hasanefendioğlu-Bayrak A, Duman D, Farooq A, King MC, Tekin M. MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes. Am J Hum Genet2010; 87(5): 679-686

[35] Hoischen A, van Bon BW, Gilissen C, Arts P, van Lier B, Steehouwer M, de Vries P, de Reuver R, Wieskamp N, Mortier G, Devriendt K, Amorim MZ, Revencu N, Kidd A, Barbosa M, Turner A, Smith J, Oley C, Henderson A, Hayes IM, Thompson EM, Brunner HG, de Vries BB, Veltman JA. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat Genet2010; 42(6): 483-485

[36] Sun Y, Almomani R, Aten E, Celli J, van der Heijden J, Venselaar H, Robertson SP, Baroncini A, Franco B, Basel-Vanagaite L, Horii E, Drut R, Ariyurek Y, den Dunnen JT, Breuning MH. Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene. Am J Hum Genet2010; 87(1): 146-153

[37] Clayton-Smith J, O’Sullivan J, Daly S, Bhaskar S, Day R, Anderson B, Voss AK, Thomas T, Biesecker LG, Smith P, Fryer A, Chandler KE, Kerr B, Tassabehji M, Lynch SA, Krajewska-Walasek M, McKee S, Smith J, Sweeney E, Mansour S, Mohammed S, Donnai D, Black G. Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome. Am J Hum Genet2011; 89(5): 675-681

[38] Ostergaard P, Simpson MA, Brice G, Mansour S, Connell FC, Onoufriadis A, Child AH, Hwang J, Kalidas K, Mortimer PS, Trembath R, Jeffery S. Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype. J Med Genet2011; 48(4): 251-255

[39] Chen WJ, Lin Y, Xiong ZQ, Wei W, Ni W, Tan GH, Guo SL, He J, Chen YF, Zhang QJ, Li HF, Lin Y, Murong SX, Xu J, Wang N, Wu ZY. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet2011; 43(12): 1252-1255

[40] Simpson MA, Irving MD, Asilmaz E, Gray MJ, Dafou D, Elmslie FV, Mansour S, Holder SE, Brain CE, Burton BK, Kim KH, Pauli RM, Aftimos S, Stewart H, Kim CA, Holder-Espinasse M, Robertson SP, Drake WM, Trembath RC. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet2011; 43(4): 303-305

[41] Isidor B, Lindenbaum P, Pichon O, Bézieau S, Dina C, Jacquemont S, Martin-Coignard D, Thauvin-Robinet C, Le Merrer M, Mandel JL, David A, Faivre L, Cormier-Daire V, Redon R, Le Caignec C. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet2011; 43(4): 306-308

[42] Hoischen A, van Bon BW, Rodríguez-Santiago B, Gilissen C, Vissers LE, de Vries P, Janssen I, van Lier B, Hastings R, Smithson SF, Newbury-Ecob R, Kjaergaard S, Goodship J, McGowan R, Bartholdi D, Rauch A, Peippo M, Cobben JM, Wieczorek D, Gillessen-Kaesbach G, Veltman JA, Brunner HG, de Vries BB. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat Genet2011; 43(8): 729-731

[43] Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Shuster EA, Aasly J, MacKenzie J, Roeber S, Kretzschmar HA, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Van Gerpen JA, Meschia JF, Levy S, Broderick DF, Graff-Radford N, Ross OA, Miller BB, Swerdlow RH, Dickson DW, Wszolek ZK. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet2012; 44(2): 200-205

[44] Boyden ED, Campos-Xavier AB, Kalamajski S, Cameron TL, Suarez P, Tanackovic G, Andria G, Ballhausen D, Briggs MD, Hartley C, Cohn DH, Davidson HR, Hall C, Ikegawa S, Jouk PS, König R, Megarbané A, Nishimura G, Lachman RS, Mortier G, Rimoin DL, Rogers RC, Rossi M, Sawada H, Scott R, Unger S, Valadares ER, Bateman JF, Warman ML, Superti-Furga A, Bonafé L. Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity. Am J Hum Genet2011; 89(6): 767-772

[45] Min BJ, Kim N, Chung T, Kim OH, Nishimura G, Chung CY, Song HR, Kim HW, Lee HR, Kim J, Kang TH, Seo ME, Yang SD, Kim DH, Lee SB, Kim JI, Seo JS, Choi JY, Kang D, Kim D, Park WY, Cho TJ. Whole-exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type. Am J Hum Genet2011; 89(6): 760-766

[46] Nosková L, Stránecký V, Hartmannová H, Přistoupilová A, Barešová V, Ivánek R, Hůlková H, Jahnová H, van der Zee J, Staropoli JF, Sims KB, Tyynelä J, Van Broeckhoven C, Nijssen PC, Mole SE, Elleder M, Kmoch S. Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. Am J Hum Genet2011; 89(2): 241-252

[47] Sirmaci A, Spiliopoulos M, Brancati F, Powell E, Duman D, Abrams A, Bademci G, Agolini E, Guo S, Konuk B, Kavaz A, Blanton S, Digilio MC, Dallapiccola B, Young J, Zuchner S, Tekin M. Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Am J Hum Genet2011; 89(2): 289-294

[48] Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M, Lakey JH, Rahman T, Wang XN, McGovern N, Pagan S, Cookson S, McDonald D, Chua I, Wallis J, Cant A, Wright M, Keavney B, Chinnery PF, Loughlin J, Hambleton S, Santibanez-Koref M, Collin M. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood2011; 118(10): 2656-2658

[49] Zimprich A, Benet-Pagès A, Struhal W, Graf E, Eck SH, Offman MN, Haubenberger D, Spielberger S, Schulte EC, Lichtner P, Rossle SC, Klopp N, Wolf E, Seppi K, Pirker W, Presslauer S, Mollenhauer B, Katzenschlager R, Foki T, Hotzy C, Reinthaler E, Harutyunyan A, Kralovics R, Peters A, Zimprich F, Brücke T, Poewe W, Auff E, Trenkwalder C, Rost B, Ransmayr G, Winkelmann J, Meitinger T, Strom TM. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet2011; 89(1): 168-175

[50] Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI, Cobb SA, Wilhoite GJ, Bacon JA, Behrouz B, Melrose HL, Hentati E, Puschmann A, Evans DM, Conibear E, Wasserman WW, Aasly JO, Burkhard PR, Djaldetti R, Ghika J, Hentati F, Krygowska-Wajs A, Lynch T, Melamed E, Rajput A, Rajput AH, Solida A, Wu RM, Uitti RJ, Wszolek ZK, Vingerhoets F, Farrer MJ. VPS35 mutations in Parkinson disease. Am J Hum Genet2011; 89(1): 162-167

[51] Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, Hojo K, Yamanishi H, Karpf AR, Wallace DC, Simon M, Lander C, Boardman LA, Cunningham JM, Smith GE, Litchy WJ, Boes B, Atkinson EJ, Middha S, B Dyck PJ, Parisi JE, Mer G, Smith DI, Dyck PJ. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet2011; 43(6): 595-600

[52] Norton N, Li D, Rieder MJ, Siegfried JD, Rampersaud E, Züchner S, Mangos S, Gonzalez-Quintana J, Wang L, McGee S, Reiser J, Martin E, Nickerson DA, Hershberger RE. Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am J Hum Genet2011; 88(3): 273-282

[53] Shi Y, Li Y, Zhang D, Zhang H, Li Y, Lu F, Liu X, He F, Gong B, Cai L, Li R, Liao S, Ma S, Lin H, Cheng J, Zheng H, Shan Y, Chen B, Hu J, Jin X, Zhao P, Chen Y, Zhang Y, Lin Y, Li X, Fan Y, Yang H, Wang J, Yang Z. Exome sequencing identifies ZNF644 mutations in high myopia. PLoS Genet2011; 7(6): e1002084

[54] Bowne SJ, Humphries MM, Sullivan LS, Kenna PF, Tam LC, Kiang AS, Campbell M, Weinstock GM, Koboldt DC, Ding L, Fulton RS, Sodergren EJ, Allman D, Millington-Ward S, Palfi A, McKee A, Blanton SH, Slifer S, Konidari I, Farrar GJ, Daiger SP, Humphries P. A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. Eur J Hum Genet2011; 19(10): 1074-1081

[55] Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet2011; 89(2): 308-312

[56] Zhou C, Zang D, Jin Y, Wu H, Liu Z, Du J, Zhang J. Mutation in ribosomal protein L21 underlies hereditary hypotrichosis simplex. Hum Mutat2011; 32(7): 710-714

[57] Le Goff C, Mahaut C, Wang LW, Allali S, Abhyankar A, Jensen S, Zylberberg L, Collod-Beroud G, Bonnet D, Alanay Y, Brady AF, Cordier MP, Devriendt K, Genevieve D, Kiper PÖ, Kitoh H, Krakow D, Lynch SA, Le Merrer M, Mégarbane A, Mortier G, Odent S, Polak M, Rohrbach M, Sillence D, Stolte-Dijkstra I, Superti-Furga A, Rimoin DL, Topouchian V, Unger S, Zabel B, Bole-Feysot C, Nitschke P, Handford P, Casanova JL, Boileau C, Apte SS, Munnich A, Cormier-Daire V. Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet2011; 89(1): 7-14

[58] O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet2011; 43(6): 585-589

[59] Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, Destrée A, di Rocco M, Héron D, Jacquemont S, Marlin S, Simon M, Tolmie J, Verloes A, Casanova JL, Munnich A, Cormier-Daire V. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet2012; 44(1): 85-88

[60] Worthey EA, Mayer AN, Syverson GD, Helbling D, Bonacci BB, Decker B, Serpe JM, Dasu T, Tschannen MR, Veith RL, Basehore MJ, Broeckel U, Tomita-Mitchell A, Arca MJ, Casper JT, Margolis DA, Bick DP, Hessner MJ, Routes JM, Verbsky JW, Jacob HJ, Dimmock DP. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med2011; 13(3): 255-262

[61] Çalışkan M, Chong JX, Uricchio L, Anderson R, Chen P, Sougnez C, Garimella K, Gabriel SB, dePristo MA, Shakir K, Matern D, Das S, Waggoner D, Nicolae DL, Ober C. Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13. Hum Mol Genet2011; 20(7): 1285-1289

[62] Züchner S, Dallman J, Wen R, Beecham G, Naj A, Farooq A, Kohli MA, Whitehead PL, Hulme W, Konidari I, Edwards YJ, Cai G, Peter I, Seo D, Buxbaum JD, Haines JL, Blanton S, Young J, Alfonso E, Vance JM, Lam BL, Peričak-Vance MA. Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa. Am J Hum Genet2011; 88(2): 201-206

[63] Becker J, Semler O, Gilissen C, Li Y, Bolz HJ, Giunta C, Bergmann C, Rohrbach M, Koerber F, Zimmermann K, de Vries P, Wirth B, Schoenau E, Wollnik B, Veltman JA, Hoischen A, Netzer C. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet2011; 88(3): 362-371

[64] Glazov EA, Zankl A, Donskoi M, Kenna TJ, Thomas GP, Clark GR, Duncan EL, Brown MA. Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia. PLoS Genet2011; 7(3): e1002027

[65] Sloan JL, Johnston JJ, Manoli I, Chandler RJ, Krause C, Carrillo-Carrasco N, Chandrasekaran SD, Sysol JR, O’Brien K, Hauser NS, Sapp JC, Dorward HM, Huizing M, Barshop BA, Berry SA, James PM, Champaigne NL, de Lonlay P, Valayannopoulos V, Geschwind MD, Gavrilov DK, Nyhan WL, Biesecker LG, Venditti CP. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet2011; 43(9): 883-886

[66] O’Sullivan J, Bitu CC, Daly SB, Urquhart JE, Barron MJ, Bhaskar SS, Martelli-Júnior H, dos Santos Neto PE, Mansilla MA, Murray JC, Coletta RD, Black GC, Dixon MJ. Whole-Exome sequencing identifies FAM20A mutations as a cause of amelogenesis imperfecta and gingival hyperplasia syndrome. Am J Hum Genet2011; 88(5): 616-620

[67] Vissers LE, Lausch E, Unger S, Campos-Xavier AB, Gilissen C, Rossi A, Del Rosario M, Venselaar H, Knoll U, Nampoothiri S, Nair M, Spranger J, Brunner HG, Bonafé L, Veltman JA, Zabel B, Superti-Furga A. Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP. Am J Hum Genet2011; 88(5): 608-615

[68] Puente XS, Quesada V, Osorio FG, Cabanillas R, Cadiñanos J, Fraile JM, Ordóñez GR, Puente DA, Gutiérrez-Fernández A, Fanjul-Fernández M, Lévy N, Freije JM, López-Otín C. Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome. Am J Hum Genet2011; 88(5): 650-656

[69] Götz A, Tyynismaa H, Euro L, Ellonen P, Hyötyläinen T, Ojala T, Hämäläinen RH, Tommiska J, Raivio T, Oresic M, Karikoski R, Tammela O, Simola KO, Paetau A, Tyni T, Suomalainen A. Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet2011; 88(5): 635-642

[70] Tariq M, Belmont JW, Lalani S, Smolarek T, Ware SM. SHROOM3 is a novel candidate for heterotaxy identified by whole exome sequencing. Genome Biol2011; 12(9): R91

[71] Snape K, Hanks S, Ruark E, Barros-Núñez P, Elliott A, Murray A, Lane AH, Shannon N, Callier P, Chitayat D, Clayton-Smith J, Fitzpatrick DR, Gisselsson D, Jacquemont S, Asakura-Hay K, Micale MA, Tolmie J, Turnpenny PD, Wright M, Douglas J, Rahman N. Mutations in CEP57 cause mosaic variegated aneuploidy syndrome. Nat Genet2011; 43(6): 527-529

[72] Saitsu H, Osaka H, Sasaki M, Takanashi J, Hamada K, Yamashita A, Shibayama H, Shiina M, Kondo Y, Nishiyama K, Tsurusaki Y, Miyake N, Doi H, Ogata K, Inoue K, Matsumoto N. Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. Am J Hum Genet2011; 89(5): 644-651

[73] Pierson TM, Adams D, Bonn F, Martinelli P, Cherukuri PF, Teer JK, Hansen NF, Cruz P, Mullikin For The Nisc Comparative Sequencing Program JC, Blakesley RW, Golas G, Kwan J, Sandler A, Fuentes Fajardo K, Markello T, Tifft C, Blackstone C, Rugarli EI, Langer T, Gahl WA, Toro C. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet2011; 7(10): e1002325

[74] Theis JL, Sharpe KM, Matsumoto ME, Chai HS, Nair AA, Theis JD, de Andrade M, Wieben ED, Michels VV, Olson TM. Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy. Circ Cardiovasc Genet2011; 4(6): 585-594

[75] Zangen D, Kaufman Y, Zeligson S, Perlberg S, Fridman H, Kanaan M, Abdulhadi-Atwan M, Abu Libdeh A, Gussow A, Kisslov I, Carmel L, Renbaum P, Levy-Lahad E. XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription. Am J Hum Genet2011; 89(4): 572-579

[76] Takata A, Kato M, Nakamura M, Yoshikawa T, Kanba S, Sano A, Kato T. Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia. Genome Biol2011; 12(9): R92

[77] Aldahmesh MA, Khan AO, Mohamed JY, Alkuraya H, Ahmed H, Bobis S, Al-Mesfer S, Alkuraya FS. Identification of ADAMTS18 as a gene mutated in Knobloch syndrome. J Med Genet2011; 48(9): 597-601

[78] Doi H, Yoshida K, Yasuda T, Fukuda M, Fukuda Y, Morita H, Ikeda S, Kato R, Tsurusaki Y, Miyake N, Saitsu H, Sakai H, Miyatake S, Shiina M, Nukina N, Koyano S, Tsuji S, Kuroiwa Y, Matsumoto N. Exome sequencing reveals a homozygous SYT14 mutation in adult-onset, autosomal-recessive spinocerebellar ataxia with psychomotor retardation. Am J Hum Genet2011; 89(2): 320-327

[79] Shaheen R, Faqeih E, Sunker A, Morsy H, Al-Sheddi T, Shamseldin HE, Adly N, Hashem M, Alkuraya FS. Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome. Am J Hum Genet2011; 89(2): 328-333

[80] Sanna-Cherchi S, Burgess KE, Nees SN, Caridi G, Weng PL, Dagnino M, Bodria M, Carrea A, Allegretta MA, Kim HR, Perry BJ, Gigante M, Clark LN, Kisselev S, Cusi D, Gesualdo L, Allegri L, Scolari F, D’Agati V, Shapiro LS, Pecoraro C, Palomero T, Ghiggeri GM, Gharavi AG. Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome. Kidney Int2011; 80(4): 389-396

[81] Barak T, Kwan KY, Louvi A, Demirbilek V, Saygı S, Tüysüz B, Choi M, Boyacı H, Doerschner K, Zhu Y, Kaymakçalan H, Yılmaz S, Bakırcıoğlu M, Cağlayan AO, Oztürk AK, Yasuno K, Brunken WJ, Atalar E, Yalçınkaya C, Dinçer A, Bronen RA, Mane S, Ozçelik T, Lifton RP, Sestan N, Bilgüvar K, Günel M. Recessive LAMC3 mutations cause malformations of occipital cortical development. Nat Genet2011; 43(6): 590-594

[82] Abou Jamra R, Philippe O, Raas-Rothschild A, Eck SH, Graf E, Buchert R, Borck G, Ekici A, Brockschmidt FF, Nöthen MM, Munnich A, Strom TM, Reis A, Colleaux L. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet2011; 88(6): 788-795

[83] Galmiche L, Serre V, Beinat M, Assouline Z, Lebre AS, Chretien D, Nietschke P, Benes V, Boddaert N, Sidi D, Brunelle F, Rio M, Munnich A, Rötig A. Exome sequencing identifies MRPL3 mutation in mitochondrial cardiomyopathy. Hum Mutat2011; 32(11): 1225-1231

[84] Ozgül RK, Siemiatkowska AM, Yücel D, Myers CA, Collin RW, Zonneveld MN, Beryozkin A, Banin E, Hoyng CB, van den Born LI, Bose R, Shen W, Sharon D, Cremers FP, Klevering BJ, den Hollander AI, Corbo JC; Collaborators: Ayuso C, Banfi S, Ben-Yosef T, de Baere E, Hamel C, Inglehearn C, Koenekoop RK, Kohl S, Leroy BP, Toomes C, Wissinger B. Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa. Am J Hum Genet2011; 89(2): 253-264

[85] Hanson D, Murray PG, O’Sullivan J, Urquhart J, Daly S, Bhaskar SS, Biesecker LG, Skae M, Smith C, Cole T, Kirk J, Chandler K, Kingston H, Donnai D, Clayton PE, Black GC. Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth. Am J Hum Genet2011; 89(1): 148-153

[86] Kalay E, Yigit G, Aslan Y, Brown KE, Pohl E, Bicknell LS, Kayserili H, Li Y, Tüysüz B, Nürnberg G, Kiess W, Koegl M, Baessmann I, Buruk K, Toraman B, Kayipmaz S, Kul S, Ikbal M, Turner DJ, Taylor MS, Aerts J, Scott C, Milstein K, Dollfus H, Wieczorek D, Brunner HG, Hurles M, Jackson AP, Rauch A, Nürnberg P, Karagüzel A, Wollnik B. CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet2011; 43(1): 23-26

[87] Bjursell MK, Blom HJ, Cayuela JA, Engvall ML, Lesko N, Balasubramaniam S, Brandberg G, Halldin M, Falkenberg M, Jakobs C, Smith D, Struys E, von Döbeln U, Gustafsson CM, Lundeberg J, Wedell A. Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. Am J Hum Genet2011; 89(4): 507-515

[88] Bredrup C, Saunier S, Oud MM, Fiskerstrand T, Hoischen A, Brackman D, Leh SM, Midtbø M, Filhol E, Bole-Feysot C, Nitschké P, Gilissen C, Haugen OH, Sanders JS, Stolte-Dijkstra I, Mans DA, Steenbergen EJ, Hamel BC, Matignon M, Pfundt R, Jeanpierre C, Boman H, Rødahl E, Veltman JA, Knappskog PM, Knoers NV, Roepman R, Arts HH. Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am J Hum Genet2011; 89(5): 634-643

[89] Aldahmesh MA, Mohamed JY, Alkuraya HS, Verma IC, Puri RD, Alaiya AA, Rizzo WB, Alkuraya FS. Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet2011; 89(6): 745-750

[90] Dauber A, Nguyen TT, Sochett E, Cole DE, Horst R, Abrams SA, Carpenter TO, Hirschhorn JN. Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia. J Clin Endocrinol Metab2012; 97(2): E268-E274

[91] Logan CV, Lucke B, Pottinger C, Abdelhamed ZA, Parry DA, Szymanska K, Diggle CP, van Riesen A, Morgan JE, Markham G, Ellis I, Manzur AY, Markham AF, Shires M, Helliwell T, Scoto M, Hübner C, Bonthron DT, Taylor GR, Sheridan E, Muntoni F, Carr IM, Schuelke M, Johnson CA. Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). Nat Genet2011; 43(12): 1189-1192

[92] Albers CA, Cvejic A, Favier R, Bouwmans EE, Alessi MC, Bertone P, Jordan G, Kettleborough RN, Kiddle G, Kostadima M, Read RJ, Sipos B, Sivapalaratnam S, Smethurst PA, Stephens J, Voss K, Nurden A, Rendon A, Nurden P, Ouwehand WH. Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome. Nat Genet2011; 43(8): 735-737

[93] de Greef JC, Wang J, Balog J, den Dunnen JT, Frants RR, Straasheijm KR, Aytekin C, van der Burg M, Duprez L, Ferster A, Gennery AR, Gimelli G, Reisli I, Schuetz C, Schulz A, Smeets DF, Sznajer Y, Wijmenga C, van Eggermond MC, van Ostaijen-Ten Dam MM, Lankester AC, van Tol MJ, van den Elsen PJ, Weemaes CM, van der Maarel SM. Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. Am J Hum Genet2011; 88(6): 796-804

[94] Sergouniotis PI, Davidson AE, Mackay DS, Li Z, Yang X, Plagnol V, Moore AT, Webster AR. Recessive mutations in KCNJ13, encoding an inwardly rectifying potassium channel subunit, cause leber congenital amaurosis. Am J Hum Genet2011; 89(1): 183-190

[95] Erlich Y, Edvardson S, Hodges E, Zenvirt S, Thekkat P, Shaag A, Dor T, Hannon GJ, Elpeleg O. Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. Genome Res2011; 21(5): 658-664

[96] Tsurusaki Y, Osaka H, Hamanoue H, Shimbo H, Tsuji M, Doi H, Saitsu H, Matsumoto N, Miyake N. Rapid detection of a mutation causing X-linked leucoencephalopathy by exome sequencing. J Med Genet2011; 48(9): 606-609

[97] Simpson MA, Deshpande C, Dafou D, Vissers LE, Woollard WJ, Holder SE, Gillessen-Kaesbach G, Derks R, White SM, Cohen-Snuijf R, Kant SG, Hoefsloot LH, Reardon W, Brunner HG, Bongers EM, Trembath RC. De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome. Am J Hum Genet2012; 90(2): 290-294

[98] Campeau PM, Kim JC, Lu JT, Schwartzentruber JA, Abdul-Rahman OA, Schlaubitz S, Murdock DM, Jiang MM, Lammer EJ, Enns GM, Rhead WJ, Rowland J, Robertson SP, Cormier-Daire V, Bainbridge MN, Yang XJ, Gingras MC, Gibbs RA, Rosenblatt DS, Majewski J, Lee BH. Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome. Am J Hum Genet2012; 90(2): 282-289

[99] Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe JW, Bain M, Lindley K, Muntoni F, Vargha-Khadem F, Dattani M, Farooqi IS, Gurnell M, Chatterjee K. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med2012; 366(3): 243-249

[100] Hood RL, Lines MA, Nikkel SM, Schwartzentruber J, Beaulieu C, Nowaczyk MJ, Allanson J, Kim CA, Wieczorek D, Moilanen JS, Lacombe D, Gillessen-Kaesbach G, Whiteford ML, Quaio CR, Gomy I, Bertola DR, Albrecht B, Platzer K, McGillivray G, Zou R, McLeod DR, Chudley AE, Chodirker BN, Marcadier J; FORGE Canada Consortium, Majewski J, Bulman DE, White SM, Boycott KM; Collaborators: Boycott K, Friedman J, Michaud J, Bernier F, Brudno M, Fernandez B, Knoppers B, Samuels M, Scherer S. Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome. Am J Hum Genet2012; 90(2): 308-313

[101] Montenegro G, Rebelo AP, Connell J, Allison R, Babalini C, D’Aloia M, Montieri P, Schüle R, Ishiura H, Price J, Strickland A, Gonzalez MA, Baumbach-Reardon L, Deconinck T, Huang J, Bernardi G, Vance JM, Rogers MT, Tsuji S, De Jonghe P, Pericak-Vance MA, Schöls L, Orlacchio A, Reid E, Züchner S. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. J Clin Invest2012; 122(2): 538-544

[102] Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, Moore AT, Loeys BL, Ghalamkarpour A, Onoufriadis A, Martinez-Corral I, Devery S, Leroy JG, van Laer L, Singer A, Bialer MG, McEntagart M, Quarrell O, Brice G, Trembath RC, Schulte-Merker S, Makinen T, Vikkula M, Mortimer PS, Mansour S, Jeffery S. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet2012; 90(2): 356-362

[103] Depienne C, Bouteiller D, Méneret A, Billot S, Groppa S, Klebe S, Charbonnier-Beaupel F, Corvol JC, Saraiva JP, Brueggemann N, Bhatia K, Cincotta M, Brochard V, Flamand-Roze C, Carpentier W, Meunier S, Marie Y, Gaussen M, Stevanin G, Wehrle R, Vidailhet M, Klein C, Dusart I, Brice A, Roze E. RAD51 haploinsufficiency causes congenital mirror movements in humans. Am J Hum Genet2012; 90(2): 301-307

[104] Lines MA, Huang L, Schwartzentruber J, Douglas SL, Lynch DC, Beaulieu C, Guion-Almeida ML, Zechi-Ceide RM, Gener B, Gillessen-Kaesbach G, Nava C, Baujat G, Horn D, Kini U, Caliebe A, Alanay Y, Utine GE, Lev D, Kohlhase J, Grix AW, Lohmann DR, Hehr U, Böhm D, Majewski J, Bulman DE, Wieczorek D, Boycott KM; Collaborators: Boycott K, Friedman J, Michaud J, Bernier F, Brudno M, Fernandez B, Knoppers B, Samuels M, Scherer S. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. Am J Hum Genet2012; 90(2): 369-377

[105] Harms MB, Sommerville RB, Allred P, Bell S, Ma D, Cooper P, Lopate G, Pestronk A, Weihl CC, Baloh RH. Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy. Ann Neurol2012; 71(3): 407-416

[106] Kirwan M, Walne AJ, Plagnol V, Velangi M, Ho A, Hossain U, Vulliamy T, Dokal I. Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. Am J Hum Genet2012; 90(5): 888-892

[107] Lee H, Graham JM Jr, Rimoin DL, Lachman RS, Krejci P, Tompson SW, Nelson SF, Krakow D, Cohn DH. Exome sequencing identifies PDE4D mutations in acrodysostosis. Am J Hum Genet2012; 90(4): 746-751

[108] Lin Z, Chen Q, Lee M, Cao X, Zhang J, Ma D, Chen L, Hu X, Wang H, Wang X, Zhang P, Liu X, Guan L, Tang Y, Yang H, Tu P, Bu D, Zhu X, Wang K, Li R, Yang Y. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J Hum Genet2012; 90(3): 558-564

[109] Bernier FP, Caluseriu O, Ng S, Schwartzentruber J, Buckingham KJ, Innes AM, Jabs EW, Innis JW, Schuette JL, Gorski JL, Byers PH, Andelfinger G, Siu V, Lauzon J, Fernandez BA, McMillin M, Scott RH, Racher H, Majewski J, Nickerson DA, Shendure J, Bamshad MJ, Parboosingh JS; Collaborators: Boycott K, Friedman J, Michaud J, Bernier F, Brudno M, Fernandez B, Knoppers B, Samuels M, Scherer S. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet2012; 90(5): 925-933

[110] Zankl A, Duncan EL, Leo PJ, Clark GR, Glazov EA, Addor MC, Herlin T, Kim CA, Leheup BP, McGill J, McTaggart S, Mittas S, Mitchell AL, Mortier GR, Robertson SP, Schroeder M, Terhal P, Brown MA. Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB. Am J Hum Genet2012; 90(3): 494-501

[111] Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, Kaname T, Naritomi K, Kawame H, Wakui K, Fukushima Y, Homma T, Kato M, Hiraki Y, Yamagata T, Yano S, Mizuno S, Sakazume S, Ishii T, Nagai T, Shiina M, Ogata K, Ohta T, Niikawa N, Miyatake S, Okada I, Mizuguchi T, Doi H, Saitsu H, Miyake N, Matsumoto N. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet2012; 44(4): 376-378

[112] Santen GW, Aten E, Sun Y, Almomani R, Gilissen C, Nielsen M, Kant SG, Snoeck IN, Peeters EA, Hilhorst-Hofstee Y, Wessels MW, den Hollander NS, Ruivenkamp CA, van Ommen GJ, Breuning MH, den Dunnen JT, van Haeringen A, Kriek M. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet2012; 44(4): 379-380

[113] Austin ED, Ma L, LeDuc C, Berman Rosenzweig E, Borczuk A, Phillips JA 3rd, Palomero T, Sumazin P, Kim HR, Talati MH, West J, Loyd JE, Chung WK. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet2012; 5(3): 336-343

[114] Qi XP, Du ZF, Ma JM, Chen XL, Zhang Q, Fei J, Wei XM, Chen D, Ke HP, Liu XZ, Li F, Chen ZG, Su Z, Jin HY, Liu WT, Zhao Y, Jiang HL, Lan ZZ, Li PF, Fang MY, Dong W, Zhang XN. Genetic diagnosis of autosomal dominant polycystic kidney disease by targeted capture and next-generation sequencing: utility and limitations. Gene2013; 516(1): 93-100

[115] Charlesworth G, Plagnol V, Holmström KM, Bras J, Sheerin UM, Preza E, Rubio-Agusti I, Ryten M, Schneider SA, Stamelou M, Trabzuni D, Abramov AY, Bhatia KP, Wood NW. Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Am J Hum Genet2012; 91(6): 1041-1050

[116] Barwick KE, Wright J, Al-Turki S, McEntagart MM, Nair A, Chioza B, Al-Memar A, Modarres H, Reilly MM, Dick KJ, Ruggiero AM, Blakely RD, Hurles ME, Crosby AH. Defective presynaptic choline transport underlies hereditary motor neuropathy. Am J Hum Genet2012; 91(6): 1103-1107

[117] Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, Oliver KL, Mazarib A, Afawi Z, Korczyn A, Plazzi G, Petrou S, Berkovic SF, Scheffer IE, Dibbens LM. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet2012; 44(11): 1188-1190

[118] Gao J, Xue J, Chen L, Ke X, Qi Y, Liu Y. Whole exome sequencing identifies a novel DFNA9 mutation, C162Y. Clin Genet2013; 83(5): 477-481

[119] Sasaki T, Niizeki H, Shimizu A, Shiohama A, Hirakiyama A, Okuyama T, Seki A, Kabashima K, Otsuka A, Ishiko A, Tanese K, Miyakawa S, Sakabe J, Kuwahara M, Amagai M, Okano H, Suematsu M, Kudoh J. Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis. J Dermatol Sci2012; 68(1): 36-44

[120] Semler O, Garbes L, Keupp K, Swan D, Zimmermann K, Becker J, Iden S, Wirth B, Eysel P, Koerber F, Schoenau E, Bohlander SK, Wollnik B, Netzer C. A mutation in the 5′-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am J Hum Genet2012; 91(2): 349-357

[121] Pohler E, Mamai O, Hirst J, Zamiri M, Horn H, Nomura T, Irvine AD, Moran B, Wilson NJ, Smith FJ, Goh CS, Sandilands A, Cole C, Barton GJ, Evans AT, Shimizu H, Akiyama M, Suehiro M, Konohana I, Shboul M, Teissier S, Boussofara L, Denguezli M, Saad A, Gribaa M, Dopping-Hepenstal PJ, McGrath JA, Brown SJ, Goudie DR, Reversade B, Munro CS, McLean WH. Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nat Genet2012; 44(11): 1272-1276

[122] Guo BR, Zhang X, Chen G, Zhang JG, Sun LD, Du WD, Zhang Q, Cui Y, Zhu J, Tang XF, Xiao R, Liu Y, Li M, Tang HY, Yang X, Cheng H, Li M, Gao M, Li P, Wang JB, Xu FP, Zuo XB, Zheng XD, Zhang XG, Yang L, Liu JJ, Wang J, Yang S, Zhang XJ. Exome sequencing identifies a COL14A1 mutation in a large Chinese pedigree with punctate palmoplantar keratoderma. J Med Genet2012; 49(9): 563-568

[123] Zhang X, Guo BR, Cai LQ, Jiang T, Sun LD, Cui Y, Hu JC, Zhu J, Chen G, Tang XF, Sun GQ, Tang HY, Liu Y, Li M, Li QB, Cheng H, Gao M, Li P, Yang X, Zuo XB, Zheng XD, Wang PG, Wang J, Wang J, Liu JJ, Yang S, Li YR, Zhang XJ. Exome sequencing identified a missense mutation of EPS8L3 in Marie Unna hereditary hypotrichosis. J Med Genet2012; 49(12): 727-730

[124] Zhang SQ, Jiang T, Li M, Zhang X, Ren YQ, Wei SC, Sun LD, Cheng H, Li Y, Yin XY, Hu ZM, Wang ZY, Liu Y, Guo BR, Tang HY, Tang XF, Ding YT, Wang JB, Li P, Wu BY, Wang W, Yuan XF, Hou JS, Ha WW, Wang WJ, Zhai YJ, Wang J, Qian FF, Zhou FS, Chen G, Zuo XB, Zheng XD, Sheng YJ, Gao JP, Liang B, Li P, Zhu J, Xiao FL, Wang PG, Cui Y, Li H, Liu SX, Gao M, Fan X, Shen SK, Zeng M, Sun GQ, Xu Y, Hu JC, He TT, Li YR, Yang HM, Wang J, Yu ZY, Zhang HF, Hu X, Yang K, Wang J, Zhao SX, Zhou YW, Liu JJ, Du WD, Zhang L, Xia K, Yang S, Wang J, Zhang XJ. Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. Nat Genet2012; 44(10): 1156-1160

[125] Liu Y, Gao M, Lv YM, Yang X, Ren YQ, Jiang T, Zhang X, Guo BR, Li M, Zhang Q, Zhang P, Zhou FS, Chen G, Yin XY, Zuo XB, Sun LD, Zheng XD, Zhang SM, Liu JJ, Zhou Y, Li YR, Wang J, Wang J, Yang HM, Yang S, Li RQ, Zhang XJ. Confirmation by exome sequencing of the pathogenic role of NCSTN mutations in acne inversa (hidradenitis suppurativa). J Invest Dermatol2011; 131(7): 1570-1572

[126] Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G, Lebel M, Gordon RD, Semmekrot BA, Poujol A, Välimäki MJ, De Ferrari ME, Sanjad SA, Gutkin M, Karet FE, Tucci JR, Stockigt JR, Keppler-Noreuil KM, Porter CC, Anand SK, Whiteford ML, Davis ID, Dewar SB, Bettinelli A, Fadrowski JJ, Belsha CW, Hunley TE, Nelson RD, Trachtman H, Cole TR, Pinsk M, Bockenhauer D, Shenoy M, Vaidyanathan P, Foreman JW, Rasoulpour M, Thameem F, Al-Shahrouri HZ, Radhakrishnan J, Gharavi AG, Goilav B, Lifton RP. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature2012; 482(7383): 98-102

[127] Shamseldin HE, Faden MA, Alashram W, Alkuraya FS. Identification of a novel DLX5 mutation in a family with autosomal recessive split hand and foot malformation. J Med Genet2012; 49(1): 16-20

[128] Khan K, Logan CV, McKibbin M, Sheridan E, Elçioglu NH, Yenice O, Parry DA, Fernandez-Fuentes N, Abdelhamed ZI, Al-Maskari A, Poulter JA, Mohamed MD, Carr IM, Morgan JE, Jafri H, Raashid Y, Taylor GR, Johnson CA, Inglehearn CF, Toomes C, Ali M. Next generation sequencing identifies mutations in Atonal homolog 7 (ATOH7) in families with global eye developmental defects. Hum Mol Genet2012; 21(4): 776-783

[129] Zhang Z, Xia W, He J, Zhang Z, Ke Y, Yue H, Wang C, Zhang H, Gu J, Hu W, Fu W, Hu Y, Li M, Liu Y. Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy. Am J Hum Genet2012; 90(1): 125-132

[130] Mitchell K, O’Sullivan J, Missero C, Blair E, Richardson R, Anderson B, Antonini D, Murray JC, Shanske AL, Schutte BC, Romano RA, Sinha S, Bhaskar SS, Black GC, Dixon J, Dixon MJ. Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus. Am J Hum Genet2012; 90(1): 69-75

[131] Walne AJ, Dokal A, Plagnol V, Beswick R, Kirwan M, de la Fuente J, Vulliamy T, Dokal I. Exome sequencing identifies MPL as a causative gene in familial aplastic anemia. Haematologica2012; 97(4): 524-528

[132] Cabral RM, Kurban M, Wajid M, Shimomura Y, Petukhova L, Christiano AM. Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome. Genomics2012; 99(4): 202-208

[133] Mayr JA, Haack TB, Graf E, Zimmermann FA, Wieland T, Haberberger B, Superti-Furga A, Kirschner J, Steinmann B, Baumgartner MR, Moroni I, Lamantea E, Zeviani M, Rodenburg RJ, Smeitink J, Strom TM, Meitinger T, Sperl W, Prokisch H. Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. Am J Hum Genet2012; 90(2): 314-320

[134] Jones MA, Ng BG, Bhide S, Chin E, Rhodenizer D, He P, Losfeld ME, He M, Raymond K, Berry G, Freeze HH, Hegde MR. DDOST mutations identified by whole-exome sequencing are implicated in congenital disorders of glycosylation. Am J Hum Genet2012; 90(2): 363-368

[135] Audo I, Bujakowska K, Orhan E, Poloschek CM, Defoort-Dhellemmes S, Drumare I, Kohl S, Luu TD, Lecompte O, Zrenner E, Lancelot ME, Antonio A, Germain A, Michiels C, Audier C, Letexier M, Saraiva JP, Leroy BP, Munier FL, Mohand-Saïd S, Lorenz B, Friedburg C, Preising M, Kellner U, Renner AB, Moskova-Doumanova V, Berger W, Wissinger B, Hamel CP, Schorderet DF, De Baere E, Sharon D, Banin E, Jacobson SG, Bonneau D, Zanlonghi X, Le Meur G, Casteels I, Koenekoop R, Long VW, Meire F, Prescott K, de Ravel T, Simmons I, Nguyen H, Dollfus H, Poch O, Léveillard T, Nguyen-Ba-Charvet K, Sahel JA, Bhattacharya SS, Zeitz C. Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet2012; 90(2): 321-330

[136] Hussain MS, Baig SM, Neumann S, Nürnberg G, Farooq M, Ahmad I, Alef T, Hennies HC, Technau M, Altmüller J, Frommolt P, Thiele H, Noegel AA, Nürnberg P. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am J Hum Genet2012; 90(5): 871-878

[137] Fiskerstrand T, Arshad N, Haukanes BI, Tronstad RR, Pham KD, Johansson S, Håvik B, Tønder SL, Levy SE, Brackman D, Boman H, Biswas KH, Apold J, Hovdenak N, Visweswariah SS, Knappskog PM. Familial diarrhea syndrome caused by an activating GUCY2C mutation. N Engl J Med2012; 366(17): 1586-1595

[138] Spiegel R, Pines O, Ta-Shma A, Burak E, Shaag A, Halvardson J, Edvardson S, Mahajna M, Zenvirt S, Saada A, Shalev S, Feuk L, Elpeleg O. Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2. Am J Hum Genet2012; 90(3): 518-523

[139] Srour M, Schwartzentruber J, Hamdan FF, Ospina LH, Patry L, Labuda D, Massicotte C, Dobrzeniecka S, Capo-Chichi JM, Papillon-Cavanagh S, Samuels ME, Boycott KM, Shevell MI, Laframboise R, Désilets V, Maranda B, Rouleau GA, Majewski J, Michaud JL; Collaborators: Boycott K, Friedman J, Michaud J, Bernier F, Brudno M, Fernandez F, Knoppers B, Samuels M, Scherer S. Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. Am J Hum Genet2012; 90(4): 693-700

[140] Polvi A, Linnankivi T, Kivelä T, Herva R, Keating JP, Mäkitie O, Pareyson D, Vainionpää L, Lahtinen J, Hovatta I, Pihko H, Lehesjoki AE. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am J Hum Genet2012; 90(3): 540-549

[141] Schossig A, Wolf NI, Fischer C, Fischer M, Stocker G, Pabinger S, Dander A, Steiner B, Tönz O, Kotzot D, Haberlandt E, Amberger A, Burwinkel B, Wimmer K, Fauth C, Grond-Ginsbach C, Koch MJ, Deichmann A, von Kalle C, Bartram CR, Kohlschütter A, Trajanoski Z, Zschocke J. Mutations in ROGDI Cause Kohlschütter-Tönz Syndrome. Am J Hum Genet2012; 90(4): 701-707

[142] Nakazawa Y, Sasaki K, Mitsutake N, Matsuse M, Shimada M, Nardo T, Takahashi Y, Ohyama K, Ito K, Mishima H, Nomura M, Kinoshita A, Ono S, Takenaka K, Masuyama R, Kudo T, Slor H, Utani A, Tateishi S, Yamashita S, Stefanini M, Lehmann AR, Yoshiura K, Ogi T. Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair. Nat Genet2012; 44(5): 586-592

[143] Khateb S, Zelinger L, Ben-Yosef T, Merin S, Crystal-Shalit O, Gross M, Banin E, Sharon D. Exome sequencing identifies a founder frameshift mutation in an alternative exon of USH1C as the cause of autosomal recessive retinitis pigmentosa with late-onset hearing loss. PLoS ONE2012; 7(12): e51566

[144] Choi BO, Park MH, Chung KW, Woo HM, Koo H, Chung HK, Choi KG, Park KD, Lee HJ, Hyun YS, Koo SK. Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2. Neurogenetics2013; 14(1): 35-42

[145] Laššuthová P, Gregor M, Sarnová L, Machalová E, Sedláček R, Seeman P. Clinical, in silico, and experimental evidence for pathogenicity of two novel splice site mutations in the SH3TC2 gene. J Neurogenet2012; 26(3-4): 413-420

[146] Lin Z, Chen Q, Shi L, Lee M, Giehl KA, Tang Z, Wang H, Zhang J, Yin J, Wu L, Xiao R, Liu X, Dai L, Zhu X, Li R, Betz RC, Zhang X, Yang Y. Loss-of-function mutations in HOXC13 cause pure hair and nail ectodermal dysplasia. Am J Hum Genet2012; 91(5): 906-911

[147] Drielsma A, Jalas C, Simonis N, Désir J, Simanovsky N, Pirson I, Elpeleg O, Abramowicz M, Edvardson S. Two novel CCDC88C mutations confirm the role of DAPLE in autosomal recessive congenital hydrocephalus. J Med Genet2012; 49(11): 708-712

[148] Lim SH, Tran-Viet KN, Yanovitch TL, Freedman SF, Klemm T, Call W, Powell C, Ravichandran A, Metlapally R, Nading EB, Rozen S, Young TL. CYP1B1, MYOC, and LTBP2 Mutations in Primary Congenital Glaucoma Patients in the United States. Am J Ophthalmol2013; 155(3): 508-517.e5

[149] Licastro D, Mutarelli M, Peluso I, Neveling K, Wieskamp N, Rispoli R, Vozzi D, Athanasakis E, D’Eustacchio A, Pizzo M, D’Amico F, Ziviello C, Simonelli F, Fabretto A, Scheffer H, Gasparini P, Banfi S, Nigro V. Molecular diagnosis of Usher syndrome: application of two different next generation sequencing-based procedures. PLoS ONE2012; 7(8): e43799

[150] Andrade DM, Paton T, Turnbull J, Marshall CR, Scherer SW, Minassian BA. Mutation of the CLN6 gene in teenage-onset progressive myoclonus epilepsy. Pediatr Neurol2012; 47(3): 205-208

[151] Olbrich H, Schmidts M, Werner C, Onoufriadis A, Loges NT, Raidt J, Banki NF, Shoemark A, Burgoyne T, Al Turki S, Hurles ME, Köhler G, Schroeder J, Nürnberg G, Nürnberg P, Chung EM, Reinhardt R, Marthin JK, Nielsen KG, Mitchison HM, Omran H.Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry. Am J Hum Genet2012; 91(4): 672-684

[152] Okumura A, Hayashi M, Shimojima K, Ikeno M, Uchida T, Takanashi JI, Okamoto N, Hisata K, Shoji H, Saito A, Furukawa T, Kishida T, Shimizu T, Yamamoto T. Whole-exome sequencing of a unique brain malformation with periventricular heterotopia, cingulate polymicrogyria and midbrain tectal hyperplasia. Neuropathology2013; 33(5): 553-560

[153] Strom SP, Gao YQ, Martinez A, Ortube C, Chen Z, Nelson SF, Nusinowitz S, Farber DB, Gorin MB. Molecular diagnosis of putative Stargardt Disease probands by exome sequencing. BMC Med Genet2012; 13(1): 67.

[154] McGrath JA, Stone KL, Begum R, Simpson MA, Dopping-Hepenstal PJ, Liu L, McMillan JR, South AP, Pourreyron C, McLean WH, Martinez AE, Mellerio JE, Parsons M. Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in Inherited Skin Fragility. Am J Hum Genet2012; 91(6): 1115-1121

[155] Aten E, Sun Y, Almomani R, Santen GW, Messemaker T, Maas SM, Breuning MH, den Dunnen JT. Exome sequencing identifies a branch point variant in Aarskog-Scott syndrome. Hum Mutat2013; 34(3): 430-434

[156] Aminkeng F. Mutations in ATP1A3 cause alternating hemiplegia of childhood. Clin Genet2013; 83(1): 32-33

[157] Marduel M, Ouguerram K, Serre V, Bonnefont-Rousselot D, Marques-Pinheiro A, Erik Berge K, Devillers M, Luc G, Lecerf JM, Tosolini L, Erlich D, Peloso GM, Stitziel N, Nitchké P, Jaïs JP; French Research Network on ADH,Abifadel M, Kathiresan S, Leren TP, Rabès JP, Boileau C, Varret M. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat2013; 34(1): 83-87

[158] Sui W, Ou M, Liang J, Ding M, Chen J, Liu W, Xiao R, Meng X, Wang L, Pan X, Zhu P, Xue W, Zhang Y, Lin H, Li F, Zhang J, Dai Y. Rapid gene identification in a Chinese osteopetrosis family by whole exome sequencing. Gene2013; 516(2): 311-315

[159] Nicolas G, Pottier C, Maltête D, Coutant S, Rovelet-Lecrux A, Legallic S, Rousseau S, Vaschalde Y, Guyant-Maréchal L, Augustin J, Martinaud O, Defebvre L, Krystkowiak P, Pariente J, Clanet M, Labauge P, Ayrignac X, Lefaucheur R, Le Ber I, Frébourg T, Hannequin D, Campion D. Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology2013; 80(2): 181-187

[160] Khuong-Quang DA, Schwartzentruber J, Westerman M, Lepage P, Finberg KE, Majewski J, Jabado N. Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy. Pediatrics 2013; 131(2): e620-e625

[161] Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, Dursun B, Bilgic B, Hanagasi H, Gurvit H, Emre M, Singleton A, Hardy J. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol2013; 70(1): 78-84

[162] Zeitz C, Jacobson SG, Hamel CP, Bujakowska K, Neuillé M, Orhan E, Zanlonghi X, Lancelot ME, Michiels C, Schwartz SB, Bocquet B; Congenital Stationary Night Blindness Consortium, Antonio A, Audier C, Letexier M, Saraiva JP, Luu TD, Sennlaub F, Nguyen H, Poch O, Dollfus H, Lecompte O, Kohl S, Sahel JA, Bhattacharya SS, Audo I. Whole-exome sequencing identifies LRIT3 mutations as a cause of autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet2013; 92(1): 67-75PMID:23246293

[163] Kalsoom UE, Klopocki E, Wasif N, Tariq M, Khan S, Hecht J, Krawitz P, Mundlos S, Ahmad W. Whole exome sequencing identified a novel zinc-finger gene ZNF141 associated with autosomal recessive postaxial polydactyly type A. J Med Genet2013; 50(1): 47-53

[164] Rios JJ, Paria N, Burns DK, Israel BA, Cornelia R, Wise CA, Ezaki M. Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly. Hum Mol Genet2013; 22(3): 444-451

[165] Schuster B, Knies K, Stoepker C, Velleuer E, Friedl R, Gottwald-Mühlhauser B, de Winter JP, Schindler D. Whole exome sequencing reveals uncommon mutations in the recently identified Fanconi anemia gene SLX4/FANCP. Hum Mutat2013; 34(1): 93-96

[166] Kennerson ML, Yiu EM, Chuang DT, Kidambi A, Tso SC, Ly C, Chaudhry R, Drew AP, Rance G, Delatycki MB, Züchner S, Ryan MM, Nicholson GA. A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum Mol Genet2013; 22(7): 1404-1416

[167] Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloğlu A, Ozen S, Sanjad S, Nelson-Williams C, Farhi A, Mane S, Lifton RP. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci USA2009; 106(45): 19096-19101

[168] Tsurusaki Y, Kobayashi Y, Hisano M, Ito S, Doi H, Nakashima M, Saitsu H, Matsumoto N, Miyake N. The diagnostic utility of exome sequencing in Joubert syndrome and related disorders. J Hum Genet2013; 58(2): 113-115

[169] Biesecker LG. Exome sequencing makes medical genomics a reality. Nat Genet2010; 42(1): 13-14

[170] Gonzaga-Jauregui C, Lupski JR, Gibbs RA. Human genome sequencing in health and disease. Annu Rev Med2012; 63(1): 35-61

[171] Ku CS, Cooper DN, Polychronakos C, Naidoo N, Wu M, Soong R. Exome sequencing: dual role as a discovery and diagnostic tool. Ann Neurol2012; 71(1): 5-14

[172] Hedges DJ, Guettouche T, Yang S, Bademci G, Diaz A, Andersen A, Hulme WF, Linker S, Mehta A, Edwards YJ, Beecham GW, Martin ER, Pericak-Vance MA, Zuchner S, Vance JM, Gilbert JR. Comparison of three targeted enrichment strategies on the SOLiD sequencing platform. PLoS ONE2011; 6(4): e18595

[173] 1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA. A map of human genome variation from population-scale sequencing. Nature2010; 467(7319): 1061-1073

[174] Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, Walenz BP, Axelrod N, Huang J, Kirkness EF, Denisov G, Lin Y, MacDonald JR, Pang AW, Shago M, Stockwell TB, Tsiamouri A, Bafna V, Bansal V, Kravitz SA, Busam DA, Beeson KY, McIntosh TC, Remington KA, Abril JF, Gill J, Borman J, Rogers YH, Frazier ME, Scherer SW, Strausberg RL, Venter JC. The diploid genome sequence of an individual human. PLoS Biol2007; 5(10): e254

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg