PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome

Abstract

Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a 'genotype first' approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.

Figure 1

Facial photographs of individuals presented in this study. Patient 1 at age 8 months (a, b), 4 years (c, d) and 7 years (e, f); patient 3 at age of diagnosis, 10 yrs (g, h, i); patient 4 at age 5 years (j); patient 5 at age 7 months (k), 2 years (l) and 4 years (m, n); patient 6 at age 5 years (o, p); patient 13 at age 8 years (q, r).

Figure 2

Graphical representation of interstitial 19p13.3 deletions and duplications; genes within the minimal region of overlap. SRO (chr19: 3979568–4093035; hg19; NCBI build 37). Patients are from our series (a); previous reports (b) and public databases, such as DECIPHER and ISCA consortium (c). Gray; duplications, Black; deletions.

Figure 3

Graphic representation of the minimal region of overlap (SRO, dashed line) responsible for macro/microcephaly in interstitial 19p13.3 microdeletion/duplication syndrome (by means of aCGH). The SRO included only one gene, PIAS4. (a) Almost all patients with macrocephaly (including relative macrocephaly, red bars) have deletions affecting PIAS4. In contrast, all patients with microcephaly (blue bars) have duplications of PIAS4 (c). Patients in panel b, with either deletions (full green bars) or duplications (striped green bars), are normocephalic. The majority of these CNAs either do not include PIAS4 or extend further towards the centromere than the individuals with head size abnormalities. Cases where PIAS4 deletion/duplication status does not correlate with head size (mainly in the normocephalic group) are illustrated by an asterisk (*). The solid black line outlines a putative region which may negate effects of PIAS4 dosage changes. Pat, Patient; nssv, ISCA consortium patients.