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.

Characterization of novel CACNA1A splice variants by RNA‐sequencing in patients with episodic or congenital ataxia

“…The presence of homozygous or compound heterozygous CACNA1A variants has been reported in severe patients with epileptic encephalopathy. 13,14 In our patient, the presentation was more severe than in the paternal family members carrying one of the variants but less severe than previously published cases with two CACNA1A variants. The variant inherited from the asymptomatic mother has a partial effect on splicing; it may not cause clinical signs on its own but enhances severity when combined with a second deleterious variant in trans.…”

2021 at European Journal of Human Genetics: the year in review

“…Orsetta Zuffardi (Pavia) identified the paper on recessive inheritance of genes previously associated with dominant disease as being clinically important [16]. The concept of dominant inheritance (a single allelic variant) is being questioned, and missense variants of the other allele, even the common ones whether they are coding or not rather than regulatory, modulate the final phenotype.…”

Biallelic CACNA1A variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

“…Recently, a CACNA1A homozygous truncating variant (p.Arg932*) was reported in a consanguineous family. Four children with these biallelic variants presented with DEE, leading to death by 6 months of age, whilst both carrier parents had symptoms consistent with EA2 (Arteche‐Lopez et al, 2021 ). Finally, and more speculatively, a family has been reported in which an insertion/deletion in exon 47, predicted to be deleterious to protein function, is associated with adult‐onset progressive myoclonic epilepsy, cognitive decline and ataxia (Lv et al, 2017 ).…”