Novel indel mutation in CDMP1 gene is associated with brachydactyly type C in a four generation Turkish family

European Human Genetics Conference 2012, Nuremberg, Almanya, 23 - 26 Haziran 2012, cilt.20, sa.1, ss.295

The cartilage derived morphogenetic protein-1 (CDMP1), also referred as

the growth/differentiation factor 5 (GDF5) gene, has been shown to be a

key regulator in the bone morphogenic protein pathway (BMP) during

skeletal and joint development. Heterozygous loss-of-function mutations

reported to cause hypoplasia/aplasia of certain skeletal elements (brachydactyly),

heterozygous gain-of-function mutations, occurring either on the

gene itself or through the loss of its inhibitor noggin, result in joint fusion

(symphalangism). Furthermore, homozygous mutations, predominantly

affecting the limbs have been described; Grebe type dysplasia, Du Pan Syndrome,

Acromesomelic Dysplasia-Hunter Thompson type. Also reported is

homozygous missense mutation presenting with brachydactyly, formulating

phenotype-genotype correlations by type and domain inconceivable, likely

due to the in􀏐luence of other factors impacting the developmental pathway.

Presently, 34 mutations dispersed throughout propeptide and chain domains

of CDMP1, associated with eight different OMIM entries, have been

described.

We ascertain here two affecteds, one female and one male, with brachdactyly

type C (MIM# 113100) presenting with disproportionate shortness of the

2nd and 3rd 􀏐ingers and hypersegmentation of the proximal and middle 2nd

and 3rd phalanges. These cases are from a family that reports an additional

8 affected members spanning across four generations. CDMP1 analysis revealed

a novel heterozygous in frame indel mutation (c.803_827del25ins25)

in the propeptide domain (p.cys268_ser276delCPSGRQPASinsLLSALLDVN).

This is the second indel mutation ascribed to the CDMP1. The previously

published indel mutation was of the out-of-frame type in homozygous state,

in the chain motif, associated with Du Pan Syndrome. Our novel mutation

further emphasizes the allelic heterogeneity of CDMP1.