Characterizing the morbid genome of ciliopathies

Abstract

BackgroundCiliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete.ResultsWe applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their “mutation load” beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population.ConclusionsOur study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1099-5) contains supplementary material, which is available to authorized users.

The genetic landscape of familial congenital hydrocephalus

“…Consistent with our prior experience in the study of genetics of recessive diseases, [21][22][23][24][25][26] we found a high hit rate of exome sequencing in the study cohort. Although recurrence in our cohort was not selected on the basis of autosomal recessive inheritance (some families had maleonly affected members), our analysis did not reveal any X-linked mutations.…”

Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood

“…Patient 4 with the apparently more severe genotype (nonsense mutation) had more extensive phenotype. This is similar to the report by Shaheen and colleagues where a patient with a severe EXOC3L2 mutation (homozygous frameshift and early truncation, p.Leu134Thrfs*25) had renal and neurological phenotype (DWM and MGS) 26. Nevertheless, patient 4 had milder poster fossa malformations than that of the patients with missense mutations.…”

“…A single subject had posterior fossa malformations (not further specified) and a homozygous variant in EXOC3L2 . The kidney disease in both, patient 4 and the first published case,26 strengthens the link of EXOC3L2 also with early-onset severe renal failure.…”

“…Our findings of a link between EXOC3L2 and DWM are supported by a report where a list of genes mutated in single patients with ciliopathies were identified and were proposed as candidate disease-associated genes. One of the patients had Meckel–Gruber syndrome (MKS), echogenic kidneys, oligohydramnion and a homozygous variant in EXOC3L2 26. In another report, fetal autopsies from 44 families with fetal malformations or fetal deaths were studied and a list of candidate disease-associated genes was proposed 27.…”

A prenatally diagnosed case of Meckel–Gruber syndrome with novel compound heterozygous pathogenic variants in the TXNDC15 gene

“…Homozygous mutations in the TXNDC15 gene causing MKS have been reported in one publication, where MKS was described in three consanguineous families: two Saudi and one Pakistani (Shaheen et al, ). The prenatal findings in one stillbirth were typical for MKS: polydactyly, enlarged cystic kidneys, and occipital encephalocele.…”