BMP2 – Brachydactyly type A2

Brachydactyly type A2 (BDA2) is an autosomal dominant disorder characterized by shortening of the middle phalanges. Noncoding duplications downstream of BMP2 have been implicated in BDA2 through segregation studies and functional assays, supporting a cis-regulatory mechanism that alters BMP2 expression.

Three independent families, including two European pedigrees and a six-generation Chinese family with 16 affected members, harbor heterozygous duplications of 5.5–5.9 kb and a novel 4.6 kb duplication at 20p12.2–12.3 downstream of BMP2. The duplication in the Chinese pedigree co-segregates perfectly with BDA2 and is absent in unaffected relatives and controls (PMID:21357617). No coding or splice-site mutations in BMP2 or adjacent genes were identified.

All reported duplications overlap a conserved noncoding enhancer 3′ of BMP2 but have distinct breakpoints, indicating a recurrent cis-regulatory hotspot rather than a single founder event. The Chinese 4.6 kb duplication refines the minimal disease-associated interval downstream of BMP2 and defines key enhancer elements.

Segregation analysis across three families demonstrates autosomal dominant inheritance with at least 16 affected relatives in one pedigree and additional cases in two European families, providing strong genetic support for BMP2 enhancer disruption in BDA2 (PMID:21357617).

Functional characterization using a luciferase reporter assay in U-2 OS and HeLa cells shows that the 2.1 kb core fragment within the 4.6 kb duplication exhibits significantly reduced enhancer activity, confirming a loss-of-function effect on BMP2 transcription (PMID:21357617).

The collective data support a model in which heterozygous cis-regulatory duplications downstream of BMP2 disrupt enhancer function, leading to haploinsufficient expression during phalangeal development and resulting in brachydactyly. Molecular testing for noncoding BMP2 duplications should be incorporated into diagnostic workflows for families with BDA2.

Key Take-home: Distal duplications downstream of BMP2 cause autosomal dominant BDA2 through disruption of a critical enhancer, providing a robust target for genetic diagnosis and counseling.

References

• Journal of medical genetics • 2011 • A 4.6 kb genomic duplication on 20p12.2-12.3 is associated with brachydactyly type A2 in a Chinese family. PMID:21357617

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