CONTEXT: Cohort specific mutations in the growth hormone (GH1) and growth hormone-releasing hormone receptor (GHRHR) genes have been reported worldwide in isolated growth hormone deficiency (IGHD) patients. However, limited data is available on ethnically diverse Indian IGHD patients. OBJECTIVE: The aim of the study was to find GH1 and GHRHR gene mutations in Indian IGHD patients from two unrelated non-consanguineous families. DESIGN: The 5' and 3' untranslated regions (UTRs) and coding regions with splice sites of the GH1 and GHRHR genes were sequenced for all patients (n=6). Family members and 20 controls were evaluated for the sequence variants identified in the index patients. Online bioinformatics tools were used to confirm mutations and their pathogenicity. RESULTS: GHRHR gene mutations were observed in all patients. Interestingly, a novel indel g.30999250_31006943delinsAGAGATCCA was observed in both the unrelated families. Three patients were homozygous for the novel indel, two were homozygous for the previously reported p.E72X mutation and one was compound heterozygous with both the mutations (indel and p.E72X) in the GHRHR gene. The novel indel has resulted in the loss of 5' regulatory region and exon 1 of the GHRHR gene impairing the GHRHR expression. All the normal family members were heterozygous either for the indel or p.E72X mutation. None of the patients had GH1 gene mutations. CONCLUSIONS: We describe a novel gross indel in the GHRHR gene resulting in the loss of 5' regulatory region and GHRHR exon 1 in four IGHD IB patients from two unrelated non-consanguineous Indian families.
CONTEXT: Cohort specific mutations in the growth hormone (GH1) and growth hormone-releasing hormone receptor (GHRHR) genes have been reported worldwide in isolated growth hormone deficiency (IGHD) patients. However, limited data is available on ethnically diverse Indian IGHDpatients. OBJECTIVE: The aim of the study was to find GH1 and GHRHR gene mutations in Indian IGHDpatients from two unrelated non-consanguineous families. DESIGN: The 5' and 3' untranslated regions (UTRs) and coding regions with splice sites of the GH1 and GHRHR genes were sequenced for all patients (n=6). Family members and 20 controls were evaluated for the sequence variants identified in the index patients. Online bioinformatics tools were used to confirm mutations and their pathogenicity. RESULTS:GHRHR gene mutations were observed in all patients. Interestingly, a novel indel g.30999250_31006943delinsAGAGATCCA was observed in both the unrelated families. Three patients were homozygous for the novel indel, two were homozygous for the previously reported p.E72X mutation and one was compound heterozygous with both the mutations (indel and p.E72X) in the GHRHR gene. The novel indel has resulted in the loss of 5' regulatory region and exon 1 of the GHRHR gene impairing the GHRHR expression. All the normal family members were heterozygous either for the indel or p.E72X mutation. None of the patients had GH1 gene mutations. CONCLUSIONS: We describe a novel gross indel in the GHRHR gene resulting in the loss of 5' regulatory region and GHRHR exon 1 in four IGHD IBpatients from two unrelated non-consanguineous Indian families.