The role of the HAND genes in Pierre Robin Sequence

Introduction: The Pierre Robin Sequence (PRS) is a potentially life-threatening human developmental anomaly characterized by congenital micrognathia, cleft of the secondary palate, and glossoptosis, leading to obstructive apnea. The mechanisms underlying its pathogenesis are yet unknown, but believed to involve multiple genetic determinants which are responsible for the range of observed malformations. Interestingly, mice with neural crest-specific deletion of Hand1 and various combinations of mutant alleles of Hand2 phenocopy those defects seen in PRS. Objective: To determine if defects in HAND1, HAND2, or cis-acting regulatory elements of HAND2 play a role in the pathogenesis of PRS. Methods: Buccal swabs from eight patients previously classified with PRS were obtained and processed using standard techniques. The samples were then subject to whole genome amplification in order to obtain sufficient DNA for analysis. Mutational analysis of the coding regions of the HAND genes, as well as a conserved enhancer element for HAND2, was performed with PCR amplification and sequencing. Results: In one of the patients, a missense mutation was found in the first exon of HAND2. This results in the substitution of a proline residue by arginine. Sequence alignment of multiple HAND2 sequences revealed the proline residue to be highly conserved at this position. This nucleotide substitution was not detected in 100 control chromosomes. Conclusion: This putative disease-associated sequence variation in HAND2 in a patient with PRS is suggestive of an essential role for the HAND genes during normal craniofacial development. Furthermore, additional analysis of those individuals in whom mutations were not found is warranted to better define other genetic determinants for this clinically challenging craniofacial disoder.

This research was supported by NIH-U24 (DE16472) and Baylor Oral Heath Foundation.