Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome

Abstract

Considering this and the high allele frequency of 0.003117 in the gnomAD database, we conclude that c.428delG represents a JBTS disease-causing variant only if present in compound heterozygous state with a more severe variant, but not in a homozygous situation.

Update of genetic variants in CEP120 and CC2D2A -- with an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies

“…In contrast, CC2D2A missense variant c.4667A>T is found in 13 unrelated cases, always in compound heterozygous state and without apparent geographical patterns. Finally, by crossing purported disease-causing variants with genomic data from the general population, we detected common variants (CC2D2A : p.Glu229del & p.Pro721Ser; CEP120 : p.Leu712Phe) that are most likely misclassified, echoing similar concerns for other ciliopathy genes (Pauli et al, 2019;Shaheen et al, 2016).…”

Sudden death in epilepsy and ectopic neurohypophysis in Joubert syndrome 23 diagnosed using SNVs/indels and structural variants pipelines on WGS data: a case report

“…This variant, was previously reported as pathogenic [5,[11][12][13]. Pathogenic variants in KIAA0586 cause two distinct autosomal recessive diseases [4][5][6][7][11][12][13]. One is the Short-rib thoracic dysplasia 14 with polydactyly (SRTD14; OMIM# 616546), a complex syndrome with skeletal and neurological manifestations [6].…”

TALPID3 in Joubert syndrome and related ciliopathy disorders

“…The developmental abnormalities exhibited by TALPID3 null model embryos of all species, such as hypotelorism, holoprosencephaly, unpatterned polysyndactyly limbs and others (Table 1) are highly characteristic of vertebrate ciliopathy mutants which lack primary cilia and have disrupted Hedgehog signalling [7]. Since 2015 a number of human patients with mutations in TALPID3/KIAA0586 have been described providing an allelic series of TALPID3/KIAA058 mutations ( Figure 2); [8][9][10][11][12][13][14][15][16]. In human patients rare homozygous mutations at c.230C>G, p.Ser77* (null) and c.1815G>A in KIAA0586 (the human ortholog of TALPID3), which appear to disrupt the TALPID3 protein before or around the essential coiled coil domain, cause a reduction of cilia on patient cells (c.1815G>A) and gestational and perinatal lethal phenotypes, respectively.…”

“…The c.428delG p.Arg143Lysfs*4 mutation is a particularly prevalent mutation accounting for 34/49 known compound heterozygous mutations, and while it would be predicted to disrupt the coiled coil domains causing a loss of TALPID3/KIAA0586 function, there are two reported cases of Joubert syndrome patients and one reported healthy individual, homozygous for the mutation [10,13,14]. This suggests the c.428delG p.Arg143Lysfs*4 mutation is instead likely to function as a hypomorphic allele, possibly through the use of an alternative start codon downstream of the c.428delG p.Arg143Lysfs*4 mutation which may produce a functional shortened protein ( Figure 2, purple arrow; NM_001244193/NP_001231122); [13]. The disparity between the severe embryonic lethal phenotype observed in null TALPID3 embryos and the relativity mild Joubert phenotype observed in the majority of TALPID3/KIAA0586 compound heterozygous mutations including those patients with a c.428delG p.Arg143Lysfs*4, support the hypothesis that this is a hypomorphic allele.…”

“…Cilia can be both actively motile such as ependymal cell cilia which line the ventricles of the brain, or 'primary' non-motile cilia, which are found on most cell types and are essential for some signalling pathways, in particular Hedgehog signalling ( Figure 1A) [7]. Most recently, this indepth understanding of the TALPID3 phenotype has aided identification of human ciliopathy patients with mutations in TALPID3/KIAA0586 [8][9][10][11][12][13][14][15][16]. Analyses of TALPID3 at the molecular level, meanwhile, have revealed that this centrosomal protein [17] has a role within mother centriole maturation prior to initiation of ciliogenesis [18] although there is evidence that TALPID3 may also have other non-ciliary centrosomal roles such as within organisation of the polarised cytoskeleton.…”