17p13.3 microduplications are associated with split-hand/foot malformation and long-bone deficiency (SHFLD)

Abstract

Split-hand/foot malformation with long-bone deficiency (SHFLD) is a relatively rare autosomal-dominant skeletal disorder, characterized by variable expressivity and incomplete penetrance. Although several chromosomal loci for SHFLD have been identified, the molecular basis and pathogenesis of most SHFLD cases are unknown. In this study we describe three unrelated kindreds, in which SHFLD segregated with distinct but overlapping duplications in 17p13.3, a region previously linked to SHFLD. In a large three-generation family, the disorder was found to segregate with a 254 kb microduplication; a second microduplication of 527 kb was identified in an affected female and her unaffected mother, and a 430 kb microduplication versus microtriplication was identified in three affected members of a multi-generational family. These findings, along with previously published data, suggest that one locus responsible for this form of SHFLD is located within a 173 kb overlapping critical region, and that the copy gains are incompletely penetrant.

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

“…The smallest region of duplication overlap significantly narrowed the critical region for the SHFLD phenotype and contained only one complete gene (BHLHA9), along with a portion of a second gene (ABR) and a putative processed transcript. Interestingly, the duplicated regions overlapped previously described duplications that were associated with developmental disabilities and infrequent limb manifestations but not SHFLD, thus raising the possibility of a complex pathogenic mechanism causing the SHFLD phenotype as opposed to a strict gene dosage effect [Armour et al, 2011].…”

“…This locus was mapped by linkage analysis in a family with autosomal dominant SHFLD [Lezirovitz et al, 2008]. Overlapping 17p13.3 microduplications ranging from 254 to 527 kb were subsequently identified by array CGH and shown to segregate with the limb phenotype in three unrelated families with SHFLD, and penetrance was incomplete [Armour et al, 2011]. The smallest region of duplication overlap significantly narrowed the critical region for the SHFLD phenotype and contained only one complete gene (BHLHA9), along with a portion of a second gene (ABR) and a putative processed transcript.…”

Split hand/foot malformation with long‐bone deficiency and BHLHA9 duplication: report of 13 new families

“…This finding had not been reported before in patients with BHLHA9 duplication. However, femoral hypoplasia seems to be present in one patient reported by Armour et al, according to the radiographs published, although this is not mentioned in the clinical description of the case .…”

“…A major locus was first identified on 17p13.3 (MIM#612576, SHFLD3) by linkage analysis of a large family presenting with autosomal dominant SHFLD . 17p13.3 duplications were then reported in unrelated families with SHFLD , the minimal 17p13.3 critical region encompassing a single gene: BHLHA9 . This gene encodes a putative basic loop helix transcription factor expressed in the limb bud mesenchyme underlying the apical ectodermal ridge in mice and zebrafish embryos.…”

Duplications ofBHLHA9are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion

“…Recently, Armour et al 17 described three SHFLD families with overlapping duplications on chromosome 17p13.3. Taken together with our results, the SRO is located between 1 117 153–1 128 916 and encompasses only a single putative gene, BHLHA9 , with a one-exon open reading frame which translates to a protein containing the characteristic structural motif of basic helix loop helix (bHLH) transcription factors.…”