19q13.11 microdeletion concomitant with ins(2;19)(p25.3;q13.1q13.4)dn in a boy: potential role of UBA2 in the associated phenotype

Abstract

The 19q13.11 microdeletion syndrome (MIM613026) is a clinically recognisable condition in which a 324-kb minimal overlapping critical region has been recently described. However, genes not included within this region, such as WTIP and UBA2, have been proposed to contribute to the clinical characteristics observed in patients. Using cytogenetic techniques, single nucleotide polymorphism arrays, and the quantitative polymerase chain reaction, we identified a novel case with a 2.49-Mb deletion derived from a de novo chromosomal rearrangement. Based on a review of the literature, we support the notion that UBA2 haploinsufficiency could contribute to the phenotype of this rare genomic disorder. UBA2 belongs to a protein complex with sumoylation activity, and several transcription factors, hormone receptors, and signalling proteins related to brain and sexual development are regulated by this post-translational modification. Additional clinical reports and further research on UBA2 molecular function are warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-014-0061-z) contains supplementary material, which is available to authorized users.

19q13.11 microdeletion: Clinical features overlapping ectrodactyly ectodermal dysplasia‐clefting syndrome phenotype

“…The CEBPA or PEPD deletion was presented nearby 70% of the reviewed patients with ectodermal dysplasia (Table S1). The most consistent finding was the observation of hypospadias and the deletion of UBA2 and WTIP genes in all male individuals with this syndrome 2, 3, 5, 6, 8, 9. UBA2 protein forms a heterodimer that behaves as a SUMO‐activating (small ubiquitin‐like modifier‐activating) enzyme for the post‐translational modification of proteins.…”

“…Zinc finger proteins, which were widely expressed, have been shown to interact with nucleic acids and to have diverse functions, such as stimulation of transcription, transcriptional repression, binding to single‐stranded DNA, binding to RNA, or bi‐functional DNA‐ and RNA‐binding activities. Their role in the development of cognitive functions has been speculated, and their haploinsufficiency could be involved in the pathogenesis of the syndrome, as the ZNF cluster at X chromosome contribute to the X‐linked intellectual disabilities 3, 9, 11…”

“…Several transcription regulators, hormone receptors, and signaling proteins are regulated and affected by this post‐translational modification. Thus, it has been suggested that SUMO modification may represent a common pathway that regulates normal craniofacial, genital development and is involved in the pathogenesis of cutis aplasia, orofacial clefting, and hypospadias 5, 7, 9, 15. Corroborating this theory, the UBA2 deletion was observed in 76% of the patients with cutis aplasia.…”

“…To date, 14 cases have been reported of deletions in the 19q13.11 region1, 2, 3, 4, 5, 6, 7, 8, 9 and additional 4 cases annotated in the Database of Chromosome Imbalance and Phenotype in Humans using Ensembl Resources — DECIPHER (patients with loss‐definitely pathogenic: 127, 317705, 339538 and 351864) 10. The main clinical characteristics are intrauterine and postnatal growth retardation, microcephaly, developmental delay/intellectual disabilities, language delay, feeding difficulties, slender habitus, cutis aplasia over the posterior occiput, and genital malformation in males (hypospadias).…”

“…Most of the reported deletions were between 1.37 and 8.16 Mb in size, with the smallest region of overlap spanning a 324‐kb region in which four zinc finger ( ZNF ) genes were located 5. However, some authors have noted the importance of other genes that are proximal to the proposed minimal overlapping region (MOR) as the cause of major features 3, 4, 7, 9. More clinical reports and research on the functions of these genes are expected to support their contribution to the phenotype.…”