Split-hand/foot malformation with long-bone deficiency and BHLHA9 duplication: Two cases and expansion of the phenotype to radial agenesis

Petit, Florence; Andrieux, Joris; Collet, Louis-Michel; Copin, Henri; Boudry-Labis, Elise; Escande, Fabienne; Manouvrier‐Hanu, Sylvie; Mathieu‐Dramard, Michèle

doi:10.1016/j.ejmg.2012.11.002

Cited by 13 publications

(11 citation statements)

References 21 publications

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“…One patient in our cohort had a radial hypoplasia (F1-IV2), and a second one had an arm reduction defect that was unfortunately insufficiently documented because of early termination of pregnancy (F12-IV8). We previously reported a radial defect in a patient carrying a larger 17p13.3 duplication encompassing BHLHA9 and two flanking genes (6). Thus, we confirm that this defect can be associated with BHLHA9 duplication, although it is an infrequent finding.…”

Section: Discussionsupporting

confidence: 83%

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

et al. 2013

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Split hand/foot malformation (SHFM) with long-bone deficiency (SHFLD, MIM#119100) is a rare condition characterized by SHFM associated with long-bone malformation usually involving the tibia. Previous published data reported several unrelated patients with 17p13.3 duplication and SHFLD. Recently, the minimal critical region had been reduced, suggesting that BHLHA9 copy number gains are associated with this limb defect. Here, we report on 13 new families presenting with ectrodactyly and harboring a BHLHA9 duplication.

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Section: Discussionsupporting

confidence: 83%

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

et al. 2013

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“…6 Mutational analysis on 17 patients affected by mesoaxial synostotic syndactyly with phalangeal reduction (OMIM 609432) revealed three neighboring homozygous missense mutations in the highly conserved DNA-binding region of the BHLHA9 protein, confirming the role of the transcription factor in limb morphogenesis. 7 We report a phenotypic and genotypic description of three SHFLD3 affected patients from the same family confirming, as reported in Petit et al 1,8 and Klopocki et al, 3 the autosomal pattern of inheritance of the disease associated with 17p13.3 microduplication that includes BHLHA9. We performed in vitro osteogenic differentiation to get new insights on the putative mineralization defect in this condition.…”

Section: Introductionsupporting

confidence: 87%

A New Split Hand/Foot Malformation with Long Bone Deficiency Familial Case

et al. 2016

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Split hand/foot malformation with long bone deficiency (SHFLD) is a congenital limb anomaly where hands and/or feet cleft and syndactyly are associated with long bone defects, usually involving the tibia. Previously published data reported that 17p13.3 chromosomal duplication, including the gene, has been associated with the distinct entity, termed SHFLD3 (OMIM 612576), inherited as an autosomal dominant trait. Here, we present a family with three members affected by SHFLD harboring duplication. We exploited in vitro differentiation system to promote proband's skin fibroblasts toward osteoblastic lineage, and we observed a slight but consistent delay in the mineralization pattern. This result possibly suggests an impairment of the osteogenic process in the affected members.

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“…In humans, hemizygous duplications of 17p13.3 segments are associated in non-Mendelian fashion with split-hand/foot malformation with long-bone deficiency (SHFLD3), and the smallest region of overlap, encasing only BHLHA9, defines this gene as a strong candidate for the bone phenotypes. 6,[8][9][10][11]34 The high degree of nonpenetrance and a sex bias are attributed to modifiers not identified yet. 11,34 The notion that functional deficiency of BHLHA9 might be responsible for SHFLD3 is also compatible with the limb expression pattern of this gene restricted to the mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos 11,14 and with the expression of a LacZ reporter gene replacing the coding region of Bhlha9 in Bhlha9 (Fingerin)/lacZ knockout/knockin mice.…”

Section: Different Clinical Phenotypes Associated With Bhlha9 Malfuncmentioning

confidence: 99%

“…2 The same chromosomal region harbors a locus for autosomal-dominant split-hand/foot malformation and long bone deficiency of variable expression and incomplete penetrance (SHFLD [MIM 612576]), 6,7 which has recently been shown to be associated with 17p13.3 duplications with a small region of overlap encompassing only a gene coding for the basic helix-loop-helix A9 transcription factor (BHLHA9 [MIM 615416]). [8][9][10][11] BHLHA9 had been predicted to contain a single exon coding for a class II basic helix-loop-helix transcription factor. 12 It emerges as a candidate gene also for MSSD because it is specifically expressed in the distal mesenchyme of E10.5-E11.5 mouse embryo limb buds, when patterning of digital rays of the autopods is taking place, and homozygous bhlha9 knockout mice displayed various degrees of simple incomplete webbing of forelimb digits 2-3 involving soft tissue, but not skeletal elements.…”

Section: Introductionmentioning

confidence: 99%

Mutations Affecting the BHLHA9 DNA-Binding Domain Cause MSSD, Mesoaxial Synostotic Syndactyly with Phalangeal Reduction, Malik-Percin Type

Malik

Perçin

Bornholdt

et al. 2014

The American Journal of Human Genetics

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Mesoaxial synostotic syndactyly, Malik-Percin type (MSSD) (syndactyly type IX) is a rare autosomal-recessive nonsyndromic digit anomaly with only two affected families reported so far. We previously showed that the trait is genetically distinct from other syndactyly types, and through autozygosity mapping we had identified a locus on chromosome 17p13.3 for this unique limb malformation. Here, we extend the number of independent pedigrees from various geographic regions segregating MSSD to a total of six. We demonstrate that three neighboring missense mutations affecting the highly conserved DNA-binding region of the basic helix-loop-helix A9 transcription factor (BHLHA9) are associated with this phenotype. Recombinant BHLHA9 generated by transient gene expression is shown to be located in the cytoplasm and the cell nucleus. Transcription factors 3, 4, and 12, members of the E protein (class I) family of helix-loop-helix transcription factors, are highlighted in yeast two-hybrid analysis as potential dimerization partners for BHLHA9. In the presence of BHLHA9, the potential of these three proteins to activate expression of an E-box-regulated target gene is reduced considerably. BHLHA9 harboring one of the three substitutions detected in MSSD-affected individuals eliminates entirely the transcription activation by these class I bHLH proteins. We conclude that by dimerizing with other bHLH protein monomers, BHLHA9 could fine tune the expression of regulatory factors governing determination of central limb mesenchyme cells, a function made impossible by altering critical amino acids in the DNA binding domain. These findings identify BHLHA9 as an essential player in the regulatory network governing limb morphogenesis in humans.

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Split-hand/foot malformation with long-bone deficiency and BHLHA9 duplication: Two cases and expansion of the phenotype to radial agenesis

Cited by 13 publications

References 21 publications

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

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

A New Split Hand/Foot Malformation with Long Bone Deficiency Familial Case

Mutations Affecting the BHLHA9 DNA-Binding Domain Cause MSSD, Mesoaxial Synostotic Syndactyly with Phalangeal Reduction, Malik-Percin Type

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