ClinVar Genomic variation as it relates to human health

Direct sequencing of exons 1, 2 and 3 of DHH gene in a patient with 46,XY karyotype and complete gonadal dysgenesis, revealed a one nucleotide deletion in exon 3 at position 1011 (c.1011delC) resulting in a substitution of an asparagine (N) residue by a lysine (K) residue at amino acid position 337 in the C-terminal part of the protein (DHhC) and a frameshift with the apparition of a premature stop codon, 24 codons after the deletion was located p.(Asn337Lysfs*24). Thus, this variation generates a truncated protein lacking the last 60 amino acids of the C-terminal region containing the determinants required for auto-processing of the precursor as well as all the essential residues fundamental for addition of a cholesterol moiety to the signaling peptide DHh-N. This mutation was found associated as a compound heterozygous mutation in DHh-N in a patient with CGD. The second mutation is a nonsense mutation which lies in the auto-catalytically processed and secreted DHh-N and gives rise to a premature stop codon leading to a truncated protein missing a part of DHh-N as well as the entire DHh-C required for auto-processing and addition of cholesterol moiety to the signaling peptide DHh-N. The novel variation p.(Asn337Lysfs*24) is not listed in gnomAD browser database (http://gnomad.broadinstitute.org) or the Human Gene Mutations Database (HGMD) (http://www.hgmd.org/) or 1000 genomes project which likely reflects a novel mutation. The pathogenicity prediction algorithm, Mutation Taster, considered the frameshift p.(Asn337Lysfs*24) mutation as disease causing. In addition, our in vitro functional assays show that this variant completely abolished auto-proteolysis of the mutant protein. In summary, the Asn337Lysfs*24 variant meets our criteria to be classified as autosomal recessive pathogenic.