Results
A compound heterozygosis of variants in the DCHS1 gene were found in the child. The first, inherited by the mother, was c.7408G>T; the second, c.3512G>A, was inherited by the father. The variants were confirmed also by Sanger sequencing both in the child and in the parents.
In silico analysis of the variants (performed by online tool mutations-taster and Alamut Visual Software) found both to be pathogenic (Schwarz et al, 2014). The first (c.7408G>T) is an unknown, never reported, variant occurring in a well-conserved domain (in this position, a different aminoacid is present only in Xenopus Tropicalis), which causes an amino acid sequence change, affecting protein structure and changing one splice site. The second (c.3512G>A) is a known, already-reported variant (dbSNP Short Genetic Variations Database, 2019; gnomeAD Browser, 2020) which occurs in a semi-conserved domain for several species (but absent in Felix Catus ,Gallus Gallus and Clostridium Elegans ), and causes amino acid sequence change, and subsequent alteration of the protein features.
Other mutation analysis software have shown some contrasting results. Running the variants through the VarCards server (VarCards Database, 2020) (which applies up to 23 different pathogenicity predictions tools), it has been suggested that the variant c.3512G>A is more likely to be pathogenic with 16 out of 23 tools predicting pathogenicity. In contrast for the variant c.7408G>T, only 7 out of 23 tools predicted this variant to be pathogenic.
No other variants were found in the gene panel analysis.
The array-CGH analysis gave a normal 46 (XX) result in the girl, and 46 (XY) and 46 (XX) results in the parents.