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

ABSTRACT: 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.

SUBMITTER: Palmer EE 

PROVIDER: S-EPMC5812890 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Palmer Elizabeth E EE   Kumar Raman R   Gordon Christopher T CT   Shaw Marie M   Hubert Laurence L   Carroll Renee R   Rio Marlène M   Murray Lucinda L   Leffler Melanie M   Dudding-Byth Tracy T   Oufadem Myriam M   Lalani Seema R SR   Lewis Andrea M AM   Xia Fan F   Tam Allison A   Webster Richard R   Brammah Susan S   Filippini Francesca F   Pollard John J   Spies Judy J   Minoche Andre E AE   Cowley Mark J MJ   Risen Sarah S   Powell-Hamilton Nina N NN   Tusi Jessica E JE   Immken LaDonna L   Nagakura Honey H   Bole-Feysot Christine C   Nitschké Patrick P   Garrigue Alexandrine A   de Saint Basile Geneviève G   Kivuva Emma E   Scott Richard H RH   Rendon Augusto A   Munnich Arnold A   Newman William W   Kerr Bronwyn B   Besmond Claude C   Rosenfeld Jill A JA   Amiel Jeanne J   Field Michael M   Gecz Jozef J  

American journal of human genetics 20171130 6

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  ...[more]