8q21.11 microdeletion syndrome: Delineation of HEY1 as a candidate gene in neurodevelopmental and cardiac defects

Abstract

Background: 8q21.11 microdeletion syndrome is a rare chromosomal disorder characterized by recurrent dysmorphic features, a variable degree of intellectual disability and ocular, cardiac and hand/feet abnormalities. To date, ZFHX4 is the only candidate gene implicated in the ocular findings. In this study, we evaluated a patient with a de novo 8q21.13-21.3 deletion to define a new small region of overlap (SRO) for this entity.

Methods: We conducted a clinical evaluation and comparative genomic hybridization (CGH) 4x44K microarrays in a patient with de novo unbalanced translocation t(8;16)(q21; q11.2).

Results: The case, a 6-year-old boy, presented dysmorphic features including an elongated face, brachycephaly with a high forehead, an underdeveloped ala, thin upper lip, micrognathia, low-set ears, hypotonia, mild intellectual disability, cortical atrophy with thin corpus callosum defect, and an atrial septal defect. No ocular abnormalities were found. Microarray analysis revealed a 9.6 Mb interstitial 8q21.11-21.3 deletion, not including the ZFHX4 gene. This microdeletion was confirmed in our patient through qPCR analysis, and both parents had a normal profile. Alignment analysis of our case defined a new SRO encompassing five genes. Among them, the HEY1 gene is involved in the embryonic development of the heart, central nervous system, and vascular system. Hrt1/Hey1 null mice show perinatal lethality due to congenital malformations of the aortic arch and its branch arteries. HEY1 has also been linked to the maintenance of neural stem cells, inhibition of oligodendrocyte differentiation, and myelin gene expression.

Conclusion: HEY1 is a candidate gene for both neurological and cardiac features of the 8q21.11 microdeletion syndrome and might, therefore, explain specific components of its pathophysiology.

Keywords: HEY1; 8q21.11 microdeletion syndrome; cardiac defect; comparative genomic hybridization; intellectual disability.

FIGURE 1

Clinical findings, brain scan, karyotype, and FISH analysis of the reported patient. (a) Photographs of the patient taken at 2 years and 6 years of age. (b) Hands and feet abnormalities. (c) Brain scan images showing cortical atrophy, predominant in bifrontal. (d) G‐banding karyotype of the patient: 46,XY,t(8;16)(q21.1;q12.13). (e) Fluorescence in situ hybridization (FISH) using probes for whole painting chromosome 8 (WCP8‐green) and chromosome 16 (WCP16‐red): WCP8 (green) paints only the normal chromosome 8 and a part of the der (16); WCP16 (red) paints only the normal chromosome 16 and a part of der (8)

FIGURE 2

Results of array CGH analysis and qPCR validation of the aberrant region. (a) Oligo array CGH profile of chromosome 8, showing decreased log2 ratio intensity values within the 8q21.13–21.3. (b) Details of genes are presented within the deleted region. (c) Validation of the 8q21.13–21.3 microdeletion by SYBR Green‐based real‐time PCR, the patient (P) presented only one copy of HEY1 and PMP2 genes while both parents (father (F) and mother (M)), and the control (C) presented two copies

FIGURE 3

Schematic representation of deletions in our patient and 19 patients from the literature and Decipher database overlapping with the reported deletion. Red bars represent the deletion sizes. The smallest region of overlap (SRO) is marked by vertical lines (chromosome 8:79647725–80520882). The Ref Seq genes are shown using UCSC Genome Browser (GRCh38)