Maternal Uniparental Isodisomy of Chromosome 2 Leading to Homozygous Variants in SPR and ZNF142: A Case Report and Review of the UPD2 Literature

Abstract

We report a 4-year-old girl with neurodevelopmental abnormalities who has maternal uniparental isodisomy of chromosome 2 leading to homozygosity for a likely pathogenic variant in SPR, and a variant of uncertain significance in ZNF142. Biallelic pathogenic variants in SPR lead to sepiapterin reductase deficiency (SRD), a dopa-responsive dystonia. Pathogenic variants in ZNF142 are associated with an autosomal recessive neurodevelopmental disorder characterized by impaired speech and hyperkinetic movements, which has significant clinical overlap with SRD. Our patient showed dramatic improvement in motor skills after treatment with levodopa. We also reviewed 67 published reports of uniparental disomy of chromosome 2 (UPD2) associated with various clinical outcomes. These include autosomal recessive disorders associated with loci on chromosome 2, infants with UPD2 whose gestations were associated with confined placental mosaicism for trisomy 2 leading to intrauterine growth restriction with good postnatal catchup growth, and normal phenotypes in children and adults with an incidental finding of either maternal or paternal UPD2. These latter reports provide support for the conclusion that genes located on chromosome 2 are not subject to imprinting. We also explore the mechanisms giving rise to UPD2.

Keywords

chromosome 2 uniparental disomy / sepiapterin reductase deficiency / genomic imprinting

References

[1] Engel E. A new genetic concept: uniparental disomy and its potential effect, isodisomy. Am J Med Genet 1980; 6(02) 137-143

[2] Del Gaudio D, Shinawi M, Astbury C, Tayeh MK, Deak KL, Raca G. ACMG Laboratory Quality Assurance Committee. Diagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG). Genet Med 2020; 22(07) 1133-1141

[3] Robinson WP. Mechanisms leading to uniparental disomy and their clinical consequences. BioEssays 2000; 22(05) 452-459

[4] Scuffins J, Keller-Ramey J, Dyer L.et al. Uniparental disomy in a population of 32,067 clinical exome trios. Genet Med 2021; 23(06) 1101-1107

[5] Silverstein S, Lerer I, Sagi M, Frumkin A, Ben-Neriah Z, Abeliovich D. Uniparental disomy in fetuses diagnosed with balanced Robertsonian translocations: risk estimate. Prenat Diagn 2002; 22(08) 649-651

[6] Richards S, Aziz N, Bale S.et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17(05) 405-424

[7] Blau N. PKU and BH4: Advances in Phenylketonuria and Tetrahydrobiopterin. SPS Publ.; 2006

[8] Friedman J, Roze E, Abdenur JE.et al. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol 2012; 71(04) 520-530

[9] Koht J, Rengmark A, Opladen T.et al. Clinical and genetic studies in a family with a novel mutation in the sepiapterin reductase gene. Acta Neurol Scand Suppl 2014; (198) 7-12

[10] Echenne B, Roubertie A, Assmann B.et al. Sepiapterin reductase deficiency: clinical presentation and evaluation of long-term therapy. Pediatr Neurol 2006; 35(05) 308-313

[11] Arrabal L, Teresa L, Sánchez-Alcudia R.et al. Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant. Neurogenetics 2011; 12(03) 183-191

[12] Leuzzi V, Carducci C, Tolve M, Giannini MT, Angeloni A, Carducci C. Very early pattern of movement disorders in sepiapterin reductase deficiency. Neurology 2013; 81(24) 2141-2142

[13] Abou Tayoun AN, Pesaran T, DiStefano MT.et al; ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI). Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum Mutat 2018; 39(11) 1517-1524

[14] Friedman J. Sepiapterin Reductase Deficiency. University of Washington;; 2015

[15] Khan K, Zech M, Morgan AT.et al. Recessive variants in ZNF142 cause a complex neurodevelopmental disorder with intellectual disability, speech impairment, seizures, and dystonia. Genet Med 2019; 21(11) 2532-2542

[16] Haudry C, de Lonlay P, Malan V.et al. Maternal uniparental disomy of chromosome 2 in a patient with a DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome. Mol Genet Metab 2012; 107(04) 700-704

[17] Harrison K, Eisenger K, Anyane-Yeboa K, Brown S. Maternal uniparental disomy of chromosome 2 in a baby with trisomy 2 mosaicism in amniotic fluid culture. Am J Med Genet 1995; 58(02) 147-151

[18] Wolstenholme J, White I, Sturgiss S, Carter J, Plant N, Goodship JA. Maternal uniparental heterodisomy for chromosome 2: detection through 'atypical' maternal AFP/hCG levels, with an update on a previous case. Prenat Diagn 2001; 21(10) 813-817

[19] Webb AL, Sturgiss S, Warwicker P, Robson SC, Goodship JA, Wolstenholme J. Maternal uniparental disomy for chromosome 2 in association with confined placental mosaicism for trisomy 2 and severe intrauterine growth retardation. Prenat Diagn 1996; 16(10) 958-962

[20] Hansen WF, Bernard LE, Langlois S.et al. Maternal uniparental disomy of chromosome 2 and confined placental mosaicism for trisomy 2 in a fetus with intrauterine growth restriction, hypospadias, and oligohydramnios. Prenat Diagn 1997; 17(05) 443-450

[21] Chen C-P, Wu FT, Chern SR.et al. Low-level mosaic trisomy 2 at amniocentesis in a pregnancy associated with positive NIPT and CVS results for trisomy 2, maternal uniparental disomy 2, perinatal progressive decrease of the aneuploid cell line, cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes, intrauterine growth restriction and a favorable fetal outcome. Taiwan J Obstet Gynecol 2023; 62(04) 571-576

[22] Shaffer LG, McCaskill C, Egli CA, Baker JC, Johnston KM. Is there an abnormal phenotype associated with maternal isodisomy for chromosome 2 in the presence of two isochromosomes?. Am J Hum Genet 1997; 61(02) 461-462

[23] Bernasconi F, Karagüzel A, Celep F.et al. Normal phenotype with maternal isodisomy in a female with two isochromosomes: i(2p) and i(2q). Am J Hum Genet 1996; 59(05) 1114-1118

[24] Keller MC, McRae AF, McGaughran JM, Visscher PM, Martin NG, Montgomery GW. Non-pathological paternal isodisomy of chromosome 2 detected from a genome-wide SNP scan. Am J Med Genet A 2009; 149A(08) 1823-1826

[25] Heide E, Heide KG, Rodewald A. Maternal uniparental disomy (UPD) for chromosome 2 discovered by exclusion of paternity. Am J Med Genet 2000; 92(04) 260-263

[26] Ou X, Liu C, Chen S.et al. Complete paternal uniparental isodisomy for Chromosome 2 revealed in a parentage testing case. Transfusion 2013; 53(06) 1266-1269

[27] Zhang X, Ding Z, He R, Qi J, Zhang Z, Cui B. Complete paternal uniparental disomy of chromosome 2 in an Asian female identified by short tandem repeats and whole genome sequencing. Cytogenet Genome Res 2019; 157(04) 197-202

[28] Chen M, Jiang J, Li C.et al. Non-pathological complete paternal uniparental isodisomy of chromosome 2 revealed in a maternity testing case. Int J Legal Med 2019; 133(04) 993-997

[29] Doniec A, Łuczak W, Wróbel M.et al. Confirmation of paternity despite three genetic incompatibilities at chromosome 2. Genes (Basel) 2021; 12(01) 62

[30] Song J, Zhu L, Zhang C, Wu Y, Wang B. A rare case of complete uniparental isodisomy of chromosome 2 with no phenotypic abnormalities. Taiwan J Obstet Gynecol 2021; 60(02) 378-379

[31] Tan X, Liu B, Yan T.et al. Prenatal diagnosis of paternal uniparental disomy for chromosome 2 in two fetuses with intrauterine growth restriction. Mol Cytogenet 2023; 16(01) 20

[32] Sifakis S, Staboulidou I, Maiz N, Velissariou V, Nicolaides KH. Outcome of pregnancies with trisomy 2 cells in chorionic villi. Prenat Diagn 2010; 30(04) 329-332

[33] Talantova OE, Koltsova AS, Tikhonov AV.et al. Prenatal detection of trisomy 2: considerations for genetic counseling and testing. Genes (Basel) 2023; 14(04) 913

[34] Talseth-Palmer BA, Bowden NA, Meldrum C.et al. A 1q44 deletion, paternal UPD of chromosome 2 and a deletion due to a complex translocation detected in children with abnormal phenotypes using new SNP array technology. Cytogenet Genome Res 2009; 124(01) 94-101

[35] Quintana A, Garabedian MJ, Wallerstein RJ. Antenatal detection of maternal unipartental disomy of chromosome 2 in a fetus with non-chromosomal, non-syndromic alobar holoprosencephaly. Am J Med Genet A 2014; 164A(01) 276-278

[36] Carmichael H, Shen Y, Nguyen TT, Hirschhorn JN, Dauber A. Whole exome sequencing in a patient with uniparental disomy of chromosome 2 and a complex phenotype. Clin Genet 2013; 84(03) 213-222

[37] Kotzot D. Advanced parental age in maternal uniparental disomy (UPD): implications for the mechanism of formation. Eur J Hum Genet 2004; 12(05) 343-346

[38] Chávez B, Valdez E, Vilchis F. Uniparental disomy in steroid 5alpha-reductase 2 deficiency. J Clin Endocrinol Metab 2000; 85(09) 3147-3150

[39] Bakker B, Bikker H, Vulsma T, de Randamie JS, Wiedijk BM, De Vijlder JJ. Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). J Clin Endocrinol Metab 2000; 85(10) 3708-3712

[40] Stratakis CA, Taymans SE, Schteingart D, Haddad BR. Segmental uniparental isodisomy (UPD) for 2p16 without clinical symptoms: implications for UPD and other genetic studies of chromosome 2. J Med Genet 2001; 38(02) 106-109

[41] Albrecht B, Mergenthaler S, Eggermann K, Zerres K, Passarge E, Eggermann T. Uniparental isodisomy for paternal 2p and maternal 2q in a phenotypically normal female with two isochromosomes, i(2p) and i(2q). J Med Genet 2001; 38(03) 214

[42] Spiekerkoetter U, Eeds A, Yue Z, Haines J, Strauss AW, Summar M. Uniparental disomy of chromosome 2 resulting in lethal trifunctional protein deficiency due to homozygous alpha-subunit mutations. Hum Mutat 2002; 20(06) 447-451

[43] Thompson DA, McHenry CL, Li Y.et al. Retinal dystrophy due to paternal isodisomy for chromosome 1 or chromosome 2, with homoallelism for mutations in RPE65 or MERTK, respectively. Am J Hum Genet 2002; 70(01) 224-229

[44] Latronico AC, Billerbeck AE, Pinto EM, Brazil D'Alva C, Arnhold IJ, Mendonca BB. Maternal isodisomy causing homozygosity for a dominant activating mutation of the luteinizing hormone receptor gene in a boy with familial male-limited precocious puberty. Clin Endocrinol (Oxf) 2003; 59(04) 533-534

[45] Petit FM, Gajdos V, Parisot F.et al. Paternal isodisomy for chromosome 2 as the cause of Crigler-Najjar type I syndrome. Eur J Hum Genet 2005; 13(03) 278-282

[46] Chevalier-Porst F, Rolland MO, Cochat P, Bozon D. Maternal isodisomy of the telomeric end of chromosome 2 is responsible for a case of primary hyperoxaluria type 1. Am J Med Genet A 2005; 132A(01) 80-83

[47] Baumer A, Basaran S, Taralczak M.et al. Initial maternal meiotic I error leading to the formation of a maternal i(2q) and a paternal i(2p) in a healthy male. Cytogenet Genome Res 2007; 118(01) 38-41

[48] Kantarci S, Ragge NK, Thomas NS.et al. Donnai-Barrow syndrome (DBS/FOAR) in a child with a homozygous LRP2 mutation due to complete chromosome 2 paternal isodisomy. Am J Med Genet A 2008; 146A(14) 1842-1847

[49] López-Garrido MP, Campos-Mollo E, Harto MA, Escribano J. Primary congenital glaucoma caused by the homozygous F261L CYP1B1 mutation and paternal isodisomy of chromosome 2. Clin Genet 2009; 76(06) 552-557

[50] Herzfeld T, Wolf N, Winter P, Hackstein H, Vater D, Müller U. Maternal uniparental heterodisomy with partial isodisomy of a chromosome 2 carrying a splice acceptor site mutation (IVS9-2A>T) in ALS2 causes infantile-onset ascending spastic paralysis (IAHSP). Neurogenetics 2009; 10(01) 59-64

[51] Hamvas A, Nogee LM, Wegner DJ.et al. Inherited surfactant deficiency caused by uniparental disomy of rare mutations in the surfactant protein-B and ATP binding cassette, subfamily a, member 3 genes. J Pediatr 2009; 155 (06) 854-859.e1

[52] Castiglia D, Castori M, Pisaneschi E.et al. Trisomic rescue causing reduction to homozygosity for a novel ABCA12 mutation in harlequin ichthyosis. Clin Genet 2009; 76(04) 392-397

[53] Baskin B, Geraghty M, Ray PN. Paternal isodisomy of chromosome 2 as a cause of long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. Am J Med Genet A 2010; 152A(07) 1808-1811

[54] Douglas GV, Wiszniewska J, Lipson MH.et al. Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis. J Hum Genet 2011; 56(12) 834-839

[55] Giovannoni I, Terracciano A, Gennari F, David E, Francalanci P, Santorelli FM. Paternal isodisomy of chromosome 2 in a child with bile salt export pump deficiency. Hepatol Res 2012; 42(03) 327-331

[56] Meijer IA, Sasarman F, Maftei C.et al. LPIN1 deficiency with severe recurrent rhabdomyolysis and persistent elevation of creatine kinase levels due to chromosome 2 maternal isodisomy. Mol Genet Metab Rep 2015; 5: 85-88

[57] Yu T, Li J, Li N.et al. Obesity and developmental delay in a patient with uniparental disomy of chromosome 2. Int J Obes 2016; 40(12) 1935-1941

[58] Dasi MA, Gonzalez-Conejero R, Izquierdo S.et al. Uniparental disomy causes deficiencies of vitamin K-dependent proteins. J Thromb Haemost 2016; 14(12) 2410-2418

[59] Shen W, Young BA, Bosworth M, Wright KE, Lamb AN, Ji Y. Prenatal detection of uniparental disomy of chromosome 2 carrying a CHRND pathogenic variant that causes lethal multiple pterygium syndrome. Clin Genet 2018; 93(06) 1248-1249

[60] Smigiel R, Rozensztrauch A, Walczak A.et al. Changing facial features in a child with GAPO syndrome caused by novel mutation in the ANTXR1 gene and uniparental disomy of chromosome 2. Clin Dysmorphol 2019; 28(04) 211-214

[61] Souzeau E, Dubowsky A, Ruddle JB, Craig JE. Primary congenital glaucoma due to paternal uniparental isodisomy of chromosome 2 and CYP1B1 deletion. Mol Genet Genomic Med 2019; 7(08) e774

[62] Guzmán-Alberto JC, Martínez-Cortes G, Rangel-Villalobos H. Inference of maternal uniparental disomy of the entire chromosome 2 from a paternity test. Int J Legal Med 2019; 133(01) 71-75

[63] Shyla A.et al. Two loci 'exclusion' of true paternity is due to genetic disorder in a child. Forensic Sci Int Genet Suppl Ser 2019; 7(01) 3-4

[64] Panasiti I, Briuglia S, Costa S, Caminiti L. Comorbidity between progressive familial intrahepatic cholestasis and atopic dermatitis in a 19-month-old child. BMJ Case Rep 2019; 12(10) e230152

[65] Zhang P, Wu B, Lu Y.et al. First maternal uniparental disomy for chromosome 2 with PREPL novel frameshift mutation of congenital myasthenic syndrome 22 in an infant. Mol Genet Genomic Med 2020; 8(03) e1144

[66] Higgins R, Jensen AN, Wachstein J.et al. Uniparental disomy of chromosome 2 unmasks new ITGA6 recessive mutation and results in a lethal junctional epidermolysis bullosa in a newborn. Acta Derm Venereol 2020; 100 (01) adv00041

[67] Horga A, Manole A, Mitchell AL.et al. Uniparental isodisomy of chromosome 2 causing MRPL44-related multisystem mitochondrial disease. Mol Biol Rep 2021; 48(03) 2093-2104

[68] Xia JK, Bai ZX, Zhao XC, Meng JJ, Chen C, Kong XD. Mitochondrial DNA depletion syndrome in a newborn with jaundice caused by DGUOK mutation and complete uniparental disomy of chromosome 2. Pediatr Neonatol 2020; 61(05) 558-560

[69] Takenouchi T, Yamada T, Kashiwagi Y, Yamaguchi Y, Uehara T, Kosaki K. Hypercoagulopathy associated with uniparental disomy of chromosome 2. J Pediatr Hematol Oncol 2020; 42(05) 370-371

[70] Szelinger S, Krate J, Ramsey K.et al; UCLA Clinical Genomics Center. Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1 . Neurol Genet 2020; 6(04) e468

[71] Shchagina O, Bessonova L, Bychkov I, Beskorovainaya T, Poliakov A. A family case of congenital myasthenic syndrome-22 induced by different combinations of molecular causes in siblings. Genes (Basel) 2020; 11(07) 821

[72] Sezer A, Kayhan G, Koç A, Ergün MA, Perçin FE. Warburg micro syndrome 1 due to segmental paternal uniparental isodisomy of chromosome 2 detected by whole-exome sequencing and homozygosity mapping. Cytogenet Genome Res 2020; 160(06) 309-315

[73] Prasov L, Ullah E, Turriff AE.et al. Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort. Am J Med Genet A 2020; 182(03) 493-497

[74] Kohl S, Baumann B, Dassie F.et al. Paternal uniparental isodisomy of chromosome 2 in a patient with CNGA3-associated autosomal recessive achromatopsia. Int J Mol Sci 2021; 22(15) 7842

[75] Schüle I, Berger U, Matysiak U.et al. A homozygous deletion of exon 5 of KYNU resulting from a maternal chromosome 2 isodisomy (UPD2) causes Catel-Manzke-Syndrome/VCRL syndrome. Genes (Basel) 2021; 12(06) 879

[76] Knapp A, Jagła M, Madetko-Talowska A.et al. Paternal uniparental disomy of chromosome 2 resulting in a concurrent presentation of Crigler-Najjar syndrome type I and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Am J Med Genet A 2022; 188(06) 1848-1852

[77] Hara-Isono K, Matsubara K, Hamada R.et al. A patient with Silver-Russell syndrome with multilocus imprinting disturbance, and Schimke immuno-osseous dysplasia unmasked by uniparental isodisomy of chromosome 2. J Hum Genet 2021; 66(11) 1121-1126

[78] Tao Y, Han D, Wei Y, Wang L, Song W, Li X. Case Report: Complete maternal uniparental disomy of chromosome 2 with a novel UNC80 splicing variant c.5609-4G> A in a Chinese patient with infantile hypotonia with psychomotor retardation and characteristic facies 2. Front Genet 2021; 12: 747422

[79] Li H, Wang L, Zhang C. A rare case of dysferlinopathy with paternal isodisomy for chromosome 2 determined by exome sequencing. Mol Genet Genomic Med 2023; 11(02) e2110

[80] Lopour MQR, Schimmenti LA, Boczek NJ, Kearney HM, Drack AV, Brodsky MC. Alström syndrome caused by maternal uniparental disomy. Am J Ophthalmol Case Rep 2022; 29: 101745

[81] Molloy B, Jones ER, Linhares ND.et al. Uniparental disomy screen of Irish rare disorder cohort unmasks homozygous variants of clinical significance in the TMCO1 and PRKRA genes. Front Genet 2022; 13: 945296

[82] Nishimura-Kinoshita N, Ohata Y, Sawai H.et al. A case of hyperphosphatemic familial tumoral calcinosis due to maternal uniparental disomy of a GALNT3 variant. Clin Pediatr Endocrinol 2023; 32(03) 161-167

[83] Jain R, Rabea F, Alfalasi R, Elabiary MW, Abou Tayoun A. Paternal uniparental isodisomy of chromosome 2 in a patient with congenital hypothyroidism: ruling out recessive inheritance or a kinship/laboratory sequencing error. J Appl Lab Med 2023; 8(05) 993-999

[84] Chen Q, Chen Y, Shi L.et al. Uniparental disomy: expanding the clinical and molecular phenotypes of whole chromosomes. Front Genet 2023; 14: 1232059

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