A heterozygous microdeletion of 20q13.13 encompassing ADNP gene in a child with Helsmoortel-van der Aa syndrome

Abstract

Helsmoortel-van der Aa (SWI/SNF autism-related or ADNP syndrome) is an autosomal dominant monogenic syndrome caused by de novo variants in the last exon of ADNP gene and no deletions have been documented to date. We report the first case of a 3 years and 10 months old boy exhibiting typical features of ADNP syndrome, including intellectual disability, autistic traits, facial dysmorphism, hyperlaxity, mood disorder, behavioral problems, and severe chronic constipation. 60K Agilent array-comparative genomic hybridization (CGH) identified a heterozygous interstitial microdeletion at 20q13.13 chromosome region, encompassing ADNP and DPM1. Taking into account the clinical phenotype of previously reported cases with ADNP single-point variants, genotype-phenotype correlation in the proband was established and the diagnosis of Helsmoortel-van der Aa syndrome was made. Our report thus confirms that ADNP haploinsufficiency is associated with Helsmoortel-van der Aa syndrome as well as highlights the utility of whole-genome array-CGH for detection of unbalanced submicroscopic chromosomal rearrangements in routine clinical setting in patients with unexplained intellectual disability and/or syndromic autism.

Fig. 1

Photographs of the face (a, c) and right profile (b) of the proband showed typical facial dysmorphic features, including: frontal bossing, high anterior hairline, broad nasal bridge, hypertelorism, wide palpebral fissures, short nose, smooth/long philtrum, small and widely spaced teeth, thin upper lip, and protruding lower lip

Fig. 2

a Overview of 1 Mb at 20q13.13 chromosome region with five reported overlapping deletions in medical literature: Decipher309, Decipher265392, Decipher257542, Decipher258702, Patient01975-5515, and index-patient. Gray shadow highlights the smallest region of overlap (SRO); the proband carried the smallest 63 kb deletion at 20q13.13 chromosome region harboring two genes ADNP and DPM1. The ADNP gene in Helsmoortel–van der Aa syndrome is highlighted in yellow. b 60K array-CGH showed a 63 kb interstitial deletion at chromosome 20q13.13 containing ADNP and DPM1. c Quantitative real-time PCR showed that the deletion occurred de novo in the proband with primers in exons 1 and 5 of ADNP gene (index-patient: purple color; mother: pink color; father: blue color; pool of male control: light blue color; pool of female control: yellow color)