ArticleGenetics in medicine : official journal of the American College of Medical Genetics2018
Interpreting the clinical significance of combined variants in multiple recessive disease genes: systematic investigation of Joubert syndrome yields little support for oligogenicity.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
17 citing papers in PubMed, 28 citations in OpenAlex.
- Tackling ciliary specialization to understand phenotypic variability in human primary ciliopathies.Journal of cell science · 2025Review
- Rare heterozygous variants in paediatric steroid resistant nephrotic syndrome - a population-based analysis of their significance.Scientific reports · 2024Article
- The dominant findings of a recessive man: from Mendel's kid pea to kidney.Pediatric nephrology (Berlin, Germany) · 2024Review
- Challenges for the implementation of next generation sequencing-based expanded carrier screening: Lessons learned from the ciliopathies.European journal of human genetics : EJHG · 2023Article
- Natural disease history of a canine model of oligogenic RPGRIP1-cone-rod dystrophy establishes variable effects of previously and newly mapped modifier loci.Human molecular genetics · 2023Article
- The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies.Annual review of genomics and human genetics · 2022Review
- Genetics behind Cerebral Disease with Ocular Comorbidity: Finding Parallels between the Brain and Eye Molecular Pathology.International journal of molecular sciences · 2022Review
- Genotype-phenotype correlates in Joubert syndrome: A review.American journal of medical genetics. Part C, Seminars in medical genetics · 2022Review
- Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome.Frontiers in genetics · 2022Review
- The morbid genome of ciliopathies: an update.Genetics in medicine : official journal of the American College of Medical Genetics · 2020Article
- Healthcare recommendations for Joubert syndrome.American journal of medical genetics. Part A · 2020Review
- Genomic Diagnosis for Pediatric Disorders: Revolution and Evolution.Frontiers in pediatrics · 2020Review
- Overinterpretation of high throughput sequencing data in medical genetics: first evidence against TMPRSS3/GJB2 digenic inheritance of hearing loss.Journal of translational medicine · 2019Article
- The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity.Translational science of rare diseases · 2019Article
- Overlap of polymicrogyria, hydrocephalus, and Joubert syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556.Neurogenetics · 2019Article
- Many Genes-One Disease? Genetics of Nephronophthisis (NPHP) and NPHP-Associated Disorders.Frontiers in pediatrics · 2017Review
- Meckel-Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances.Frontiers in pediatrics · 2017Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
PurposeNext-generation sequencing (NGS) often identifies multiple rare predicted-deleterious variants (RDVs) in different genes associated with a recessive disorder in a given patient. Such variants have been proposed to contribute to digenicity/oligogenicity or "triallelism" or to act as genetic modifiers.MethodsUsing the recessive ciliopathy Joubert syndrome (JBTS) as a model, we investigated these possibilities systematically, relying on NGS of known JBTS genes in a large JBTS and two control cohorts.Results65% of affected individuals had a recessive genetic cause, while 4.9% were candidates for di-/oligogenicity, harboring heterozygous RDVs in two or more genes, compared with 4.2-8% in controls (P = 0.66-0.21). Based on Exome Aggregation Consortium (ExAC) allele frequencies, the probability of cumulating RDVs in any two JBTS genes is 9.3%. We found no support for triallelism, as no unaffected siblings carried the same biallelic RDVs as their affected relative. Sixty percent of individuals sharing identical causal RDVs displayed phenotypic discordance. Although 38% of affected individuals harbored RDVs in addition to the causal mutations, their presence did not correlate with phenotypic severity.ConclusionOur data offer little support for triallelism or digenicity/oligogenicity as clinically relevant inheritance modes in JBTS. While phenotypic discordance supports the existence of genetic modifiers, identifying clinically relevant modifiers remains challenging.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.