A family with brachydactyly mental retardation syndrome with a missense variant in HDAC4

Abstract

Brachydactyly mental retardation syndrome (BDMR) or chromosome 2q37 deletion syndrome is a genetic disorder caused by 2q37 deletion or haploinsufficiency of histone deacetylase 4 (HDAC4). The HDAC4 gene is responsible for major BDMR phenotypes. The symptoms of BDMR include mild-to-moderate intellectual disability, seizures, autism spectrum disorder, short stature, obesity, and facial dysmorphism. Here, we report a family (n = 5) with BDMR who had a missense variant of HDAC4. Four affected individuals [5-yr-old girl (index case); 15- and 3-yr-old siblings; and father] had mild intellectual disability, three of the four affected individuals had short stature and mild cardiac anomalies, and two of the four affected individuals had hypothyroidism. Whole-exome sequencing and analyses of the index case and her family revealed an allelic variant in the HDAC4 gene (NM_001378414.1:c.2204G>A:p. Arg735Gln). A healthy family member (mother) did not have the missense variant. To our knowledge, this is the first report of a missense variation in HDAC4 that is associated with BDMR.

Keywords: 2q37 deletion syndrome; 2q37.3; Brachydactyly mental retardation syndrome; HDAC4.

Fig. 1.

(a) Photograph showing the hands of the index case at five years of age reveals bilateral clinodactyly of the little fingers. (b) Radiograph of the index case at five years of age shows shortened middle phalanges of the little fingers. (c) An allelic variant of c.2204G>A was confirmed in the HDAC4 gene of the four symptomatic family members by Sanger sequencing. An arrow in the family tree indicates the index case.