Expansion of the Clinical and Molecular Spectrum of LINS1 ‐Associated Disease

LINS1 gene plays a role in cognition and brain development. Mutations in this gene have been identified as the cause of a neurodevelopmental disorder as well as dysmorphisms, motor symptoms, behavioral problems, seizures, microcephaly, mitral valve prolapse, and Q‐T prolongation. We recruited two related families with a total of four children affected by LINS1 ‐associated neurodevelopmental disorder. All four subjects have global developmental delay. Congenital heart disease is prominent: Tetralogy of Fallot in two (one with a discontinuous left pulmonary artery), left‐sided cardiac hypoplasia with bicuspid aortic valve and membranous VSD in one, and transient aortic dilation with residual mild annular dilation and a small coronary fistula in one. Hyperopia is present in three; the fourth, younger than 2 years, is not yet tested. Dysmorphic features include a long face in two, midface hypoplasia in one, and frontal bossing with prominent eyes in one. All subjects are homozygous for a canonical splice acceptor variant in LINS1 (NM_001040616.3:c.490‐1G>C); parents are heterozygous carriers. We extend the phenotypic spectrum of LINS1 ‐associated neurodevelopmental disorder to include significant structural cardiac anomalies and refractive errors. These observations support consideration of cardiac and ophthalmologic evaluation in individuals with biallelic pathogenic LINS1 variants.