Exome sequencing identifies mutations in ABCD1 and DACH2in two brothers with a distinct phenotype

Abstract

BackgroundWe report on two brothers with a distinct syndromic phenotype and explore the potential pathogenic cause.MethodsCytogenetic tests and exome sequencing were performed on the two brothers and their parents. Variants detected by exome sequencing were validated by Sanger sequencing.ResultsThe main phenotype of the two brothers included congenital language disorder, growth retardation, intellectual disability, difficulty in standing and walking, and urinary and fecal incontinence. To the best of our knowledge, no similar phenotype has been reported previously. No abnormalities were detected by G-banding chromosome analysis or array comparative genomic hybridization. However, exome sequencing revealed novel mutations in the ATP-binding cassette, sub-family D member 1 (ABCD1) and Dachshund homolog 2 (DACH2) genes in both brothers. The ABCD1 mutation was a missense mutation c.1126G > C in exon 3 leading to a p.E376Q substitution. The DACH2 mutation was also a missense mutation c.1069A > T in exon 6, leading to a p.S357C substitution. The mother was an asymptomatic heterozygous carrier. Plasma levels of very-long-chain fatty acids were increased in both brothers, suggesting a diagnosis of adrenoleukodystrophy (ALD); however, their phenotype was not compatible with any reported forms of ALD. DACH2 plays an important role in the regulation of brain and limb development, suggesting that this mutation may be involved in the phenotype of the two brothers.ConclusionThe distinct phenotype demonstrated by these two brothers might represent a new form of ALD or a new syndrome. The combination of mutations in ABCD1 and DACH2 provides a plausible mechanism for this phenotype.

Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription

“…In particular, the nullisomic regions deleted in families CHM1 and CHM2 contain genes that exert different functions, such as the ZNF711 gene, which encodes a zinc-finger sequence-specific DNA binding factor [38][39][40]. Additionally deleted in both our families are POF1B, which seems to play a role in the etiology of premature ovarian failure [41], and DACH2, with an important role in the regulation of brain and limb development and presumed to be implicated in syndromic mental retardation [41,42].…”

Xq21.1q21.31 Duplication in Two Male Siblings

“…Increased expression of DACH2 might also contribute to the phenotype associated with Xq21 duplication. [Zhang et al, 2014]. However, a number of males hemizygous for this variant are recorded in the gnomAD database, which suggests that this may be a benign variant found in the East Asian population.…”

A Novel Chromosomal Translocation Identified due to Complex Genetic Instability in iPSC Generated for Choroideremia

“…However, it is unlikely that the DACH2 deletion impacts the phenotype, as studies in the mouse Dach2 -/- model suggest that there is a compensation of its function by another member of the same family, Dach1 [35] (murine homologue of human DACH1 ; MIM 603803). Moreover, in cases where DACH2 variants have been identified in individuals with disease phenotypes, variants in a second gene were also identified [36,37]. Therefore, to date, there is no conclusive evidence linking DACH2 to a clinical phenotype.…”