ClinVar Genomic variation as it relates to human health

In a large kindred with dominant growth hormone deficiency (IGHD2; 173100) Gertner et al. (1998) detected a heterozygous G-to-A transition at nucleotide 6664 in exon 5 of the GH1 gene, resulting in an arg183-to-his substitution (R183H). Hess et al. (2007) studied the phenotype-genotype correlation of subjects with IGHD2 caused by an R183H mutation in the GH1 gene in 34 affected members of 2 large families. Twenty-four of the 52 members from family 1 and 10 of the 14 from family 2 carried the same mutation in a heterozygous state. The affected subjects in family 1 were significantly shorter (-2.6 vs -0.1 standard deviation score (SDS), p less than 0.0001) and had significantly lower IGF1 (147440) serum levels (-1.9 vs -0.5 SDS, p less than 0.0001), compared with family members with a normal genotype. The affected adults exhibited great variability in their stature, ranging from -4.5 to -1.0 SD (mean -2.8 SDS), with 5 members being of normal height (greater than -2 SDS). Twelve children were diagnosed with IGHD. Two affected children had normal peak GH levels, although 1 of these subsequently demonstrated GH insufficiency. The affected children from both families exhibited large variability in their height, growth velocity, delay in bone age, age at diagnosis, peak GH response, and IGF1 levels. Hess et al. (2007) concluded that these detailed phenotypic analyses show the variable expressivity of patients bearing the R183H mutation, reflecting the spectrum of GH deficiency in affected patients, even within families, and the presence of additional genes modifying height determination. (less)