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.