Mosaicism of a Truncating Variant of <b><i>CASK</i></b> Causes Congenital Heart Disease and Neurodevelopmental Disorder

Abstract

<b><i>Introduction:</i></b> Calcium/calmodulin-dependent serine protein kinase (<i>CASK</i>) gene mutations cause microcephaly with pontine and cerebellar hypoplasia (MICPCH) and X-linked intellectual disability. Congenital heart disease (CHD) is a rare complication reported in only 4 male patients with full loss-of-function mutations. Here, we report the first male patient with mosaicism of a truncating variant of <i>CASK</i> complicated by CHD. <b><i>Case Presentation:</i></b> The patient is a 6-year-old male with MICPCH, ventricular septal defect, and developmental delay. He achieved rolling over but can not speak meaningful words. We identified a somatic mosaic variant of <i>CASK</i>: c.[725=/G&#x3e;A], p.(W242*) and high mosaic ratios of 90% and 84% for mutant alleles in peripheral blood lymphocytes and skin fibroblasts, respectively. His developmental delay was severe but milder than that of previously reported CHD patients. <b><i>Discussion:</i></b> Truncating <i>CASK</i> variants may be associated with CHD, even in a mosaic state, and even a low normal allele ratio could lengthen survivorship.