ClinVar

In 2 apparently unrelated families with brachydactyly type A1 (BDA1; 112500) studied by Drinkwater (1908, 1914), McCready et al. (2002) found the same asp100-to-asn (D100N) mutation due to a 298G-A transition in the IHH gene.

Giordano et al. (2003) identified the D100N mutation in members of a 3-generation Italian family affected with mild brachydactyly type A1 and no other clinical abnormality except for short stature.

McCready et al. (2005) identified the D100N mutation in descendants of the family with brachydactyly originally described by Farabee (1903) and restudied by Haws and McKusick (1963). Using 16 markers spanning the IHH locus, they identified a common haplotype between this family and the 2 kindreds studied by Drinkwater (1908, 1914) and McCready et al. (2002), suggesting a common founder.

In affected members of a large 4-generation Chinese family with brachydactyly, Zhu et al. (2007) identified heterozygosity for the D100N mutation of the IHH gene. Haplotype analysis revealed that this family carried different alleles at 3 microsatellite markers and 2 intragenic SNPs of the previously published Farabee-Drinkwater haplotype (McCready et al., 2005), indicating that the D100N mutation most likely arose more than once. Zhu et al. (2007) stated that the D100N mutation had been found independently in 7 BDA1 families, whereas all other IHH mutations had been found only once, and suggested that nucleotide 298G represents a mutation hotspot.

In 6 affected members of an 8-generation New Zealand family with BDA1, Byrnes et al. (2009) identified heterozygosity for the D100N mutation in the IHH gene. Haplotype analysis and comparison with the DNA of the BDA1 families studied by Drinkwater (1908, 1914) and Farabee (1903) revealed the presence of a common shared haplotype between markers D2S2250 and D2S1323. Other clinical features observed in the extended New Zealand family included lumbar lordosis, extra teeth, and a shortened fifth metacarpal.