Mesomelia-synostoses syndrome: contiguous deletion syndrome, SULF1 haploinsufficiency or enhancer adoption?

TL;DR

This paper investigates the genetic basis of Mesomelia-Synostoses Syndrome, suggesting it may be caused by SULF1 haploinsufficiency or enhancer adoption due to TAD boundary disruption.

Contribution

The study proposes that MSS is caused by SULF1 haploinsufficiency or enhancer adoption, excluding SLCO5A1 as a candidate gene.

Findings

A 21 kb deletion in the 15q12 region was identified as likely pathogenic, involving GABRA5.

The chr8 translocation breakpoint truncates SLCO5A1, excluding it as a candidate for MSS.

MSS deletions remove a TAD boundary, suggesting SULF1 haploinsufficiency or enhancer adoption as possible causes.

Abstract

Mesomelia-Synostoses Syndrome (MSS)(OMIM 600,383) is a rare autosomal dominant disorder characterized by mesomelic limb shortening, acral synostoses and multiple congenital malformations which is described as a contiguous deletion syndrome involving the two genes SULF1 and SLCO5A1. The study of apparently balanced chromosomal rearrangements (BCRs) is a cytogenetic strategy used to identify candidate genes associated with Mendelian diseases or abnormal phenotypes. With the improved development of genomic technologies, new methods refine this search, allowing better delineation of breakpoints as well as more accurate genotype-phenotype correlation.

We present a boy with a global development deficit, delayed speech development and an ASD (Asperger) family history, with an apparently balanced “de novo” reciprocal translocation [t(1;8)(p32.2;q13)dn]. The cytogenetic molecular study identified a likely pathogenic deletion of 21 kb in the 15q12 region, while mate pair sequencing identified gene-truncations at both the 1p32.2 and 8q13 translocation breakpoints.

The identification of a pathogenic alteration on 15q12 involving GABRA5 was likely the main cause of the ASD-phenotype. Importantly, the chr8 translocation breakpoint truncating SLCO5A1 exclude SLCO5A1 as a candidate for MSS, leaving SULF1 as the primary candidate. However, the deletions observed in MSS remove a topological associated domain (TAD) boundary separating SULF1 and SLCO5A1. Hence, Mesomelia-Synostoses syndrome is either caused by haploinsufficiency of SULF1 or ectopic enhancer effects where skeletal/chrondrogenic SULF1 enhancers drive excopic expression of developmental genes in adjacent TADs including PRDM14, NCOA2 and/or EYA1.

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