Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5

Abstract

Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and medicine. Panoramic variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic variation. Here, a Pakistani family with parental consanguinity was presented, characterized with severe intellectual disability (ID), spastic paraplegia, and deafness. Homozygosity mapping, integrated single nucleotide polymorphism (SNP) array, whole-exome sequencing, and whole-genome sequencing were performed, and homozygous variants in TMEM141 (c.270G>A, p.Trp90*), DDHD2 (c.411+767_c.1249-327del), and LHFPL5 (c.250delC, p.Leu84*) were identified. A Tmem141^{p.Trp90*/p.Trp90*} mouse model was generated. Behavioral studies showed impairments in learning ability and motor coordination. Brain slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje cells. Transmission electron microscopy showed abnormal mitochondrial morphology. Furthermore, studies on a human in vitro neuronal model (SH-SY5Y cells) with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function, possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse model. Conclusively, panoramic variation analysis revealed that multilocus genomic variations of TMEM141, DDHD2, and LHFPL5 together caused variable phenotypes in patient. Notably, the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.

Key words： neurodevelopmental disorder; autosomal recessive intellectual disability; consanguinity; spastic paraplegia; hearing loss; TMEM141

Acknowledgements

We would like to thank all the individuals for their collaboration. This work was financially supported by the National Natural Science Foundation of China (NSFC) (Nos. 82001221 and 81788101), the National Key Research and Development Program of China (Nos. 2022YFC2703900 and 2022YFC2703903), and the CAMS Innovation Fund for Medical Sciences (CIFMS) (Nos. 2021-I2M-1-018, 2022-I2M-JB-004 and 2017-I2M-B&R-05).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1006-x and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Liwei Sun, Xueting Yang, Amjad Khan, Xue Yu, Han Zhang, Shirui Han, Xiaerbati Habulieti, Yang Sun, Rongrong Wang, and Xue Zhang declare that they have no conflict of interest.

The study was approved by Peking Union Medical College Institutional Review Board and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from the patient and her family members. All institutional and national guidelines for the care and use of laboratory animals were followed.

References

1 Parenti I, Rabaneda LG, Schoen H, Novarino G. Neurodevelopmental disorders: from genetics to functional pathways. Trends Neurosci 2020; 43(8): 608–621

2 Vissers LE, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet 2016; 17(1): 9–18

3 Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil 2011; 32(2): 419–436

4 Mefford HC, Batshaw ML, Hoffman EP. Genomics, intellectual disability, and autism. N Engl J Med 2012; 366(8): 733–743

5 Hu H, Kahrizi K, Musante L, Fattahi Z, Herwig R, Hosseini M, Oppitz C, Abedini SS, Suckow V, Larti F, Beheshtian M, Lipkowitz B, Akhtarkhavari T, Mehvari S, Otto S, Mohseni M, Arzhangi S, Jamali P, Mojahedi F, Taghdiri M, Papari E, Soltani Banavandi MJ, Akbari S, Tonekaboni SH, Dehghani H, Ebrahimpour MR, Bader I, Davarnia B, Cohen M, Khodaei H, Albrecht B, Azimi S, Zirn B, Bastami M, Wieczorek D, Bahrami G, Keleman K, Vahid LN, Tzschach A, Gärtner J, Gillessen-Kaesbach G, Varaghchi JR, Timmermann B, Pourfatemi F, Jankhah A, Chen W, Nikuei P, Kalscheuer VM, Oladnabi M, Wienker TF, Ropers HH, Najmabadi H. Genetics of intellectual disability in consanguineous families. Mol Psychiatry 2019; 24(7): 1027–1039

6 Nazli A, Safdar A, Saleem A, Akhtar M, Brady LI, Schwartzentruber J, Tarnopolsky MA. A mutation in the TMEM65 gene results in mitochondrial myopathy with severe neurological manifestations. Eur J Hum Genet 2017; 25(6): 744–751

7 ČížkováA V, Stránecký JA, Mayr M, Tesarová V, Havlícková J, Paul R, Ivánek AW, Kuss H, Hansíková V, Kaplanová M, Vrbacký H, Hartmannová L, Nosková T, Honzík Z, Drahota M, Magner K, Hejzlarová W, Sperl J, Zeman J, Houstek S. TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet 2008; 40(11): 1288–1290

8 Thomas Q, Motta M, Gautier T, Zaki MS, Ciolfi A, Paccaud J, Girodon F, Boespflug-Tanguy O, Besnard T, Kerkhof J, McConkey H, Masson A, Denommé-Pichon AS, Cogné B, Trochu E, Vignard V, El It F, Rodan LH, Alkhateeb MA, Jamra RA, Duplomb L, Tisserant E, Duffourd Y, Bruel AL, Jackson A, Banka S, McEntagart M, Saggar A, Gleeson JG, Sievert D, Bae H, Lee BH, Kwon K, Seo GH, Lee H, Saeed A, Anjum N, Cheema H, Alawbathani S, Khan I, Pinto-Basto J, Teoh J, Wong J, Sahari UBM, Houlden H, Zhelcheska K, Pannetier M, Awad MA, Lesieur-Sebellin M, Barcia G, Amiel J, Delanne J, Philippe C, Faivre L, Odent S, Bertoli-Avella A, Thauvin C, Sadikovic B, Reversade B, Maroofian R, Govin J, Tartaglia M, Vitobello A. Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly. Am J Hum Genet 2022; 109(10): 1909–1922

9 Tábara LC, Al-Salmi F, Maroofian R, Al-Futaisi AM, Al-Murshedi F, Kennedy J, Day JO, Courtin T, Al-Khayat A, Galedari H, Mazaheri N, Protasoni M, Johnson M, Leslie JS, Salter CG, Rawlins LE, Fasham J, Al-Maawali A, Voutsina N, Charles P, Harrold L, Keren B, Kunji ERS, Vona B, Jelodar G, Sedaghat A, Shariati G, Houlden H, Crosby AH, Prudent J, Baple EL. TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia. Brain 2022; 145(9): 3095–3107

10 Brancati F, Camerota L, Colao E, Vega-Warner V, Zhao X, Zhang R, Bottillo I, Castori M, Caglioti A, Sangiuolo F, Novelli G, Perrotti N, Otto EA; Undiagnosed Disease Network Italy. Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome. Eur J Hum Genet 2018; 26(9): 1266–1271

11 Coon H, Darlington T, Pimentel R, Smith KR, Huff CD, Hu H, Jerominski L, Hansen J, Klein M, Callor WB, Byrd J, Bakian A, Crowell SE, McMahon WM, Rajamanickam V, Camp NJ, McGlade E, Yurgelun-Todd D, Grey T, Gray D. Genetic risk factors in two Utah pedigrees at high risk for suicide. Transl Psychiatry 2013; 3(11): e325

12 Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, Walkiewicz M, Bi W, Xiao R, Ding Y, Xia F, Beaudet AL, Muzny DM, Gibbs RA, Boerwinkle E, Eng CM, Sutton VR, Shaw CA, Plon SE, Yang Y, Lupski JR. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med 2017; 376(1): 21–31

13 Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37(9): e67

14 Martell JD, Deerinck TJ, Sancak Y, Poulos TL, Mootha VK, Sosinsky GE, Ellisman MH, Ting AY. Engineered ascorbate peroxidase as a genetically encoded reporter for electron microscopy. Nat Biotechnol 2012; 30(11): 1143–1148

15 Li D, Wei H, Zhang Z, Liang W, Stokke BG. Oriental reed warbler (Acrocephalus orientalis) nest defence behaviour towards brood parasites and nest predators. Behaviour 2015; 152(12–13): 1601–1621

16 Zhang Z, Hong J, Zhang S, Zhang T, Sha S, Yang R, Qian Y, Chen L. Postpartum estrogen withdrawal impairs hippocampal neurogenesis and causes depression- and anxiety-like behaviors in mice. Psychoneuroendocrinology 2016; 66: 138–149

17 Ballesta JJ, del Pozo C, Castelló-Banyuls J, Faura CC. Selective down-regulation of α4β2 neuronal nicotinic acetylcholine receptors in the brain of uremic rats with cognitive impairment. Exp Neurol 2012; 236(1): 28–33

18 Abrahamsson T, Lalanne T, Watt AJ, Sjöström PJ. Long-term potentiation by theta-burst stimulation using extracellular field potential recordings in acute hippocampal slices. Cold Spring Harb Protoc 2016; 2016(6): pdb.prot091298

19 He Q, Sha S, Sun L, Zhang J, Dong M. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway. Biochem Biophys Res Commun 2016; 476(4): 196–203

20 Polli JE, Rekhi GS, Augsburger LL, Shah VP. Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets. J Pharm Sci 1997; 86(6): 690–700

21 Gonzalez M, Nampoothiri S, Kornblum C, Oteyza AC, Walter J, Konidari I, Hulme W, Speziani F, Schöls L, Züchner S, Schüle R. Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54). Eur J Hum Genet 2013; 21(11): 1214–1218

22 Kalay E, Li Y, Uzumcu A, Uyguner O, Collin RW, Caylan R, Ulubil-Emiroglu M, Kersten FF, Hafiz G, van Wijk E, Kayserili H, Rohmann E, Wagenstaller J, Hoefsloot LH, Strom TM, Nürnberg G, Baserer N, den Hollander AI, Cremers FP, Cremers CW, Becker C, Brunner HG, Nürnberg P, Karaguzel A, Basaran S, Kubisch C, Kremer H, Wollnik B. Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss. Hum Mutat 2006; 27(7): 633–639

23 Platzer K, Sticht H, Edwards SL, Allen W, Angione KM, Bonati MT, Brasington C, Cho MT, Demmer LA, Falik-Zaccai T, Gamble CN, Hellenbroich Y, Iascone M, Kok F, Mahida S, Mandel H, Marquardt T, McWalter K, Panis B, Pepler A, Pinz H, Ramos L, Shinde DN, Smith-Hicks C, Stegmann APA, Stöbe P, Stumpel CTRM, Wilson C, Lemke JR, Di Donato N, Miller KG, Jamra R. De novo variants in MAPK8IP3 cause intellectual disability with variable brain anomalies. Am J Hum Genet 2019; 104(2): 203–212

24 Dulovic-Mahlow M, Trinh J, Kandaswamy KK, Braathen GJ, Di Donato N, Rahikkala E, Beblo S, Werber M, Krajka V, BuskØL, Baumann H, Al-Sannaa NA, Hinrichs F, Affan R, Navot N, Al Balwi MA, Oprea G, Holla ØL, Weiss MER, Jamra RA, Kahlert AK, Kishore S, Tveten K, Vos M, Rolfs A, Lohmann K. De novo variants in TAOK1 cause neurodevelopmental disorders. Am J Hum Genet 2019; 105(1): 213–220

25 Wang R, Han S, Khan A, Zhang X. Molecular analysis of twelve Pakistani families with nonsyndromic or syndromic hearing loss. Genet Test Mol Biomarkers 2017; 21(5): 316–321

26 Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ, Ben-Salem S, de Bot ST, Nijhof B, van de Vondervoort II, van der Graaf M, Nobau AC, Otte-Höller I, Vermeer S, Smith AC, Humphreys P, Schwartzentruber J, Ali BR, Al-Yahyaee SA, Tariq S, Pramathan T, Bayoumi R, Kremer HP, van de Warrenburg BP, van den Akker WM, Gilissen C, Veltman JA, Janssen IM, Vulto-van Silfhout AT, van der Velde-Visser S, Lefeber DJ, Diekstra A, Erasmus CE, Willemsen MA, Vissers LE, Lammens M, van Bokhoven H, Brunner HG, Wevers RA, Schenck A, Al-Gazali L, de Vries BB, de Brouwer AP. Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet 2012; 91(6): 1073–1081

27 Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol 2013; 126(3): 307–328

28 Marx S, Dal Maso T, Chen JW, Bury M, Wouters J, Michiels C, Le Calvé B. Transmembrane (TMEM) protein family members: Poorly characterized even if essential for the metastatic process. Semin Cancer Biol 2020; 60: 96–106

29 Norat P, Soldozy S, Sokolowski JD, Gorick CM, Kumar JS, Chae Y, Yağmurlu K, Prada F, Walker M, Levitt MR, Price RJ, Tvrdik P, Kalani MYS. Mitochondrial dysfunction in neurological disorders: exploring mitochondrial transplantation. NPJ Regen Med 2020; 5(1): 22

30 Kann O, Kovács R. Mitochondria and neuronal activity. Am J Physiol Cell Physiol 2007; 292(2): C641–C657

31 Dutta D, Briere LC, Kanca O, Marcogliese PC, Walker MA, High FA, Vanderver A, Krier J, Carmichael N, Callahan C, Taft RJ, Simons C, Helman G, Network UD, Wangler MF, Yamamoto S, Sweetser DA, Bellen HJ. De novo mutations in TOMM70, a receptor of the mitochondrial import translocase, cause neurological impairment. Hum Mol Genet 2020; 29(9): 1568–1579