The prevalence and phenotypic range associated with biallelic PKDCC variants.

PKDCC encodes a component of Hedgehog signalling required for normal chondrogenesis and skeletal development. Although biallelic PKDCC variants have been implicated in rhizomelic shortening of limbs with variable dysmorphic features, this association was based on just two patients. In this study, data from the 100 000 Genomes Project was used in conjunction with exome sequencing and panel-testing results accessed via international collaboration to assemble a cohort of eight individuals from seven independent families with biallelic PKDCC variants. The allelic series included six frameshifts, a previously described splice-donor site variant and a likely pathogenic missense variant observed in two families that was supported by in silico structural modelling. Database queries suggested that the prevalence of this condition is between 1 of 127 and 1 of 721 in clinical cohorts with skeletal dysplasia of unknown aetiology. Clinical assessments, combined with data from previously published cases, indicate a predominantly upper limb involvement. Micrognathia, hypertelorism and hearing loss appear to be commonly co-occurring features. In conclusion, this study strengthens the link between biallelic inactivation of PKDCC and rhizomelic limb-shortening and will enable clinical testing laboratories to better interpret variants in this gene.

Clinical and molecular evidence of possible digenic inheritance for MFN2/GDAP1 genes in Charcot-Marie-Tooth disease.

Charcot Marie Tooth disease (CMT) is a progressive motor and sensory polyneuropathy, it is characterized by a very heterogeneous molecular basis and phenotype. MFN2 and GDAP1 participate in mitochondrial energy metabolism and the rare coinheritance of its pathogenic variants has been associated with a cumulative effect in the observed phenotype. We describe a patient with a severe axonal CMT and inherited heterozygous MFN2 (p.Leu741Val) and GDAP1 (p.Gln163*) variants. In accordance with a possible digenic inheritance, none of the heterozygous carriers in his family were symptomatic or exhibited electrophysiological abnormalities. We also review all of the previously reported patients with coinheritance of variants in these two genes; similar to our patient, all exhibit a predominantly axonal severe CMT phenotype. Our findings expand the genotypic spectrum of CMT and further support that digenic inheritance should be considered for analyzing and counseling CMT patients.