Novel<i>KIAA1033</i>/<i>WASHC4</i>mutations in three patients with syndromic intellectual disability and a review of the literature

<jats:title>Abstract</jats:title><jats:p>In 2011,<jats:italic>KIAA1033</jats:italic>/<jats:italic>WASHC4</jats:italic>was associated with autosomal recessive intellectual disability (ARID) in a large consanguineous family comprising seven affected individuals with moderate ID and short stature. Since then, no other cases of<jats:italic>KIAA1033</jats:italic>variants have been reported. Here we describe three additional patients (from two unrelated families) with syndromic ID due to compound heterozygous<jats:italic>KIAA1033</jats:italic>variants ascertained by exome sequencing (ES). Two sisters, aged 4 and 5.5 years, had a stop‐gain and a missense variants, each inherited from one parent (p.(Gln442*) and p.(Asp1048Gly)). Both had learning disabilities, macrocephaly, dysmorphic features, skeletal anomalies, and subependymal heterotopic nodules. In addition, the younger sibling had a congenital absence of the right internal carotid and bilateral sensorineural hearing loss. The third patient was aged 34 years and had two missense variants, one inherited from each parent (p.(Lys1079Arg) and p.(His503Arg)). This patient presented with mild ID, short stature, and microcephaly.<jats:italic>KIAA1033</jats:italic>encodes a large protein (WASHC4), which is part of the WASH complex. The WASH complex is involved in the regulation of the fission of tubules that serve as transport intermediates during endosome sorting. Another member of the WASH complex, KIAA0196/WASHC5, has already been implicated in ARID with brain and cardiac malformations, under the designation of 3C or Ritscher‐Schinzel syndrome (MIM#20210). ES has proved efficient for finding replications of genes with insufficient data in the literature to be defined as new OMIM genes. We conclude that<jats:italic>KIAA1033</jats:italic>is responsible for a heterogeneous ARID phenotype, and additional description will be needed to refine the clinical phenotype.</jats:p>