A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations

• DOI: 10.1016/j.ajhg.2017.10.009
• Publication Date: 2017-11-30T17:01:09Z
• Authors: Elizabeth E. Palmer; Raman Kumar; Christopher T. Go...; Marie Shaw; Laurence Hubert; Renee Carroll; Marlène Rio; Lucinda Murray; Melanie Leffler; Tracy Dudding-Byth; Myriam Oufadem; Seema R. Lalani; Andrea M. Lewis; Fan Xia; Allison Tam; Richard Webster; Susan Brammah; Francesca Filippini; John Pollard; Judy Spies; Andre E. Minoche; Mark J. Cowley; Sarah Risen; Nina N. Powell-Ha...; Jessica E. Tusi; LaDonna Immken; Honey Nagakura; Christine Bole-Fe...; Patrick Nitschké; Alexandrine Garrigue; Geneviève de Sain...; Emma Kivuva; Richard H. Scott; Augusto Rendon; Arnold Munnich; William Newman; Bronwyn Kerr; Claude Besmond; Jill A. Rosenfeld; Jeanne Amiel; Michael Field; Jozef Gecz
• Keywords: nonsense-mediated decay; Central Nervous System; 0301 basic medicine; 32 Biomedical and Clinical Sciences; Congenital; 2.1 Biological and endogenous factors; acromelic frontonasal dysostosis (AFND); anzsrc-for: 31 Biological Sciences; Pediatric; anzsrc-for: 42 Health Sciences; High-Throughput Nucleotide Sequencing; Wessex Classification Subject Headings::Oncology. Pathology.::Genetics; 3. Good health; DNA-Binding Proteins; Limb Deformities; Codon, Nonsense; intellectual disabilities; de novo; 572; limb malformations; Intellectual and Developmental Disabilities (IDD); anzsrc-for: 110311 Medical Genetics (excl. Cancer Genetics); Limb Deformities, Congenital; Neurocognitive Disorders; autism; 610; ubiquitination; 03 medical and health sciences; recurrent; anzsrc-for: 32 Biomedical and Clinical Sciences; Clinical Research; Intellectual Disability; Peripheral Nervous System; Genetics; genomics; Journal Article; Humans; Codon; DDD Study; anzsrc-for: 111403 Paediatrics; Neurosciences; 42 Health Sciences; Brain Disorders; Nonsense; anzsrc-for: 11 Medical and Health Sciences; anzsrc-for: 06 Biological Sciences; Congenital Structural Anomalies; ZSWIM6; epilepsy; exome sequencing; Mandibulofacial Dysostosis; 31 Biological Sciences

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.