Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

• DOI: 10.1016/j.ajhg.2021.08.003
• Publication Date: 2021-10-08T21:38:09Z
• Authors: Elodie M. Richard; Somayeh Bakhtiari; Ashley P.L. Marsh; Rauan Kaiyrzhanov; Matias Wagner; Sheetal Shetty; Alex Pagnozzi; Sandra M. Nordlie; Brandon S. Guida; Patricia Cornejo; Helen Magee; James Liu; Bethany Y. Norton; Richard I. Webster; Lisa Worgan; Hakon Hakonarson; Jiankang Li; Yiran Guo; Mahim Jain; Alyssa Blesson; Lance H. Rodan; Mary-Alice Abbott; Anne Comi; Julie S. Cohen; Bader Alhaddad; Thomas Meitinger; Dominic Lenz; Andreas Ziegler; Urania Kotzaeridou; Theresa Brunet; Anna Chassevent; Constance Smith-H...; Joseph Ekstein; Tzvi Weiden; Andreas Hahn; Nazira Zharkinbekova; Peter Turnpenny; Arianna Tucci; Melissa Yelton; Rita Horvath; Serdal Gungor; Semra Hiz; Yavuz Oktay; Hanns Lochmuller; Marcella Zollino; Manuela Morleo; Giuseppe Marangi; Vincenzo Nigro; Annalaura Torella; Michele Pinelli; Simona Amenta; Ralf A. Husain; Benita Grossmann; Marion Rapp; Claudia Steen; Iris Marquardt; Mona Grimmel; Ute Grasshoff; G. Christoph Korenke; Marta Owczarek-Li...; John Neidhardt; Francesca Clement...; Cecilia Mancini; Dianela Judith Cl...; Kirsty McWalter; Amber Begtrup; Amy Crunk; Maria J. Guillen ...; Richard Person; Rhonda E. Schnur; Maria Margherita ...; Florian Kreuder; Pasquale Striano; Federico Zara; Wendy K. Chung; Warren A. Marks; Clare L. van Eyk; Dani L. Webber; Mark A. Corbett; Kelly Harper; Jesia G. Berry; Alastair H. MacLe...; Jozef Gecz; Marco Tartaglia; Vincenzo Salpietro; John Christodoulou; Jan Kaslin; Sergio Padilla-Lopez; Kaya Bilguvar; Alexander Munchau; Zubair M. Ahmed; Robert B. Hufnagel; Michael C. Fahey; Reza Maroofian; Henry Houlden; Heinrich Sticht; Shrikant M. Mane; Aboulfazl Rad; Barbara Vona; Sheng Chih Jin; Tobias B. Haack; Christine Makowski; Yoel Hirsch; Saima Riazuddin; Michael C. Kruer
• Keywords: Adult; Male; AAA+ superfamily; ATPase; cerebral palsy; epilepsy; intellectual disability; movement disorder; neurodevelopmental disorder; sensorineural hearing loss; SPATA5L1; ATPases Associated with Diverse Cellular Activities; Adolescent; Adult; Alleles; Animals; Cerebral Palsy; Child, Preschool; Epilepsy; Female; Hearing Loss; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Muscle Spasticity; Rats; Young Adult; Genetic Predisposition to Disease; Genetic Variation; Adolescent; AAA+ superfamily; ATPase; cerebral palsy; epilepsy; intellectual disability; movement disorder; neurodevelopmental disorder; sensorineural hearing loss; SPATA5L1; Aaa+ Superfamily ; Atpase ; Spata5l1 ; Cerebral Palsy ; Epilepsy ; Intellectual Disability ; Movement Disorder ; Neurodevelopmental Disorder ; Sensorineural Hearing Loss; Pediatrics; sensorineural hearing loss; Young Adult; 03 medical and health sciences; Intellectual Disability; Medicine and Health Sciences; ATPase; Animals; Humans; Genetic Predisposition to Disease; SPATA5L1; Child; Preschool; Hearing Loss; Alleles; cerebral palsy; 0303 health sciences; Epilepsy; Cerebral Palsy; Infant, Newborn; Genetic Variation; Infant; Newborn; neurodevelopmental disorder; Rats; 3. Good health; intellectual disability; Muscle Spasticity; Child, Preschool; epilepsy; ATPases Associated with Diverse Cellular Activities; Female; movement disorder; AAA+ superfamily

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.