Premium
A mendelian form of neural tube defect caused by a de novo null variant in SMARCC1 in an identical twin
Author(s) -
Al Mutairi Fuad,
Alzahrani Fatema,
Ababneh Farouq,
Kashgari Amna A.,
Alkuraya Fowzan S.
Publication year - 2018
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25152
Subject(s) - exencephaly , neural tube , genetics , mendelian inheritance , biology , null allele , neurulation , allele , neural tube defect , encephalocele , mutation , chromatin , nonsense mutation , gene , missense mutation , fetus , gastrulation , embryogenesis , pregnancy , embryo , teratology
Neural tube defects (NTDs) are among the most common birth defects in humans and yet their molecular etiology remains poorly understood. NTDs are believed to result from the complex interaction of environmental factors with a multitude of genetic risk factors in a classical multifactorial disease model. Mendelian forms of NTDs in which single variants are sufficient to cause the disease are extremely rare. We report a monozygotic twin with severe NTDs (occipital encephalocele and myelomeningocele) and a shared de novo, likely truncating, variant in SMARCC1 . RTPCR analysis suggests the potential null nature of the variant attributed to nonsense‐mediated decay. SMARCC1 is extremely constrained in humans and encodes a highly conserved core chromatin remodeler, BAF155. Mice that are heterozygous for a null allele or homozygous for a hypomorphic allele develop severe NTDs in the form of exencephaly. This is the first report of SMARCC1 mutation in humans, and it shows a critical and conserved requirement for intact BAF chromatin remodeling complex in neurulation. Ann Neurol 2018;83:433–436