Biallelic variants in genes previously associated with dominant inheritance: CACNA1A, RET and SLC20A2

Abstract

A subset of families with co-dominant or recessive inheritance has been described in several genes previously associated with dominant inheritance. Those recessive families displayed similar, more severe, or even completely different phenotypes to their dominant counterparts. We report the first patients harboring homozygous disease-related variants in three genes that were previously associated with dominant inheritance: a loss-of-function variant in the CACNA1A gene and two missense variants in the RET and SLC20A2 genes, respectively. All patients presented with a more severe clinical phenotype than the corresponding typical dominant form. We suggest that co-dominant or recessive inheritance for these three genes could explain the phenotypic differences from those documented in their cognate dominant phenotypes. Our results reinforce that geneticists should be aware of the possible different forms of inheritance in genes when WES variant interpretation is performed. We also evidence the need to refine phenotypes and inheritance patterns associated with genes in order to avoid failures during WES analysis and thus, raising the WES diagnostic capacity in the benefit of patients.

Fig. 1. Family 1: CACNA1A gene.

A Family 1 pedigree and genotypes; wild type (wt); mutant allele (mt). B Schematic structure of the Cav2.1 channel (adapted from Damaj et al. [17]). The red start illustrates the p.(Arg932*) variant detected in our family in the CACNA1A gene; the green starts indicate the variants described in Reinson et al. [31].

Fig. 2. Family 2: RET gene.

A Family 2 pedigree and genotypes; wild type (wt); mutant allele (mt). B Schematic domain structure of the RET protein (adapted from Wang et al. [49] and Wu et al. 2019 [50]). The red star indicates the position of the variant p.(Asp571Asn) detected in the RET gene in our family. The regions were MEN2A and MEN2B causal variants cluster are indicated with blue bars. C Multiple sequence alignment of residues adjacent to amino acid 571 of the RET protein from human (h), mouse (m), rat (r), drosophila (d), and chicken (c). The tool Clustal Omega was used for multiple alignments (https://www.ebi.ac.uk/Tools/msa/clustalo/). SP signal peptide, CLD cadherin-like domain, CRD Cysteine-rich domain, TM transmembrane, TKD tyrosine kinase domain.

Fig. 3. Family 3: SLC20A2 gene.

A Family 3 pedigree and genotypes; wild type (wt); mutant allele (mt). B Schematic representation of the SLC20A2 protein (adapted from Hsu SC et al. 2013 [42]). Blue bars illustrate the N-and C-terminal ProDom domain (N-PD001131 and C-PD001131 respectively) of the protein. The red star indicates the position of the variant p.(Arg71Cys) in the SLC20A2 gene detected in our family. C Cranial computed tomography (CT) scan of the homozygous patient showing extensive areas of calcification in the frontal white matter and basal ganglia. D Normal cranial CT scan of her asymptomatic heterozygous sister (II:6).