Reduced penetrance in human inherited disease

Shawky, Rabah M.

doi:10.1016/j.ejmhg.2014.01.003

Cited by 38 publications

(23 citation statements)

References 86 publications

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“…Another possible mechanism is “position effect” with variable expression of genes near the translocation or other identified rearrangement breakpoints [11,12]. Finally, reduced penetrance is a well-known observation in many dominant traits [13,14]. …”

Section: Introductionmentioning

confidence: 99%

Accurate Breakpoint Mapping in Apparently Balanced Translocation Families with Discordant Phenotypes Using Whole Genome Mate-Pair Sequencing

et al. 2017

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Familial apparently balanced translocations (ABTs) segregating with discordant phenotypes are extremely challenging for interpretation and counseling due to the scarcity of publications and lack of routine techniques for quick investigation. Recently, next generation sequencing has emerged as an efficacious methodology for precise detection of translocation breakpoints. However, studies so far have mainly focused on de novo translocations. The present study focuses specifically on familial cases in order to shed some light to this diagnostic dilemma. Whole-genome mate-pair sequencing (WG-MPS) was applied to map the breakpoints in nine two-way ABT carriers from four families. Translocation breakpoints and patient-specific structural variants were validated by Sanger sequencing and quantitative Real Time PCR, respectively. Identical sequencing patterns and breakpoints were identified in affected and non-affected members carrying the same translocations. PTCD1, ATP5J2-PTCD1, CADPS2, and STPG1 were disrupted by the translocations in three families, rendering them initially as possible disease candidate genes. However, subsequent mutation screening and structural variant analysis did not reveal any pathogenic mutations or unique variants in the affected individuals that could explain the phenotypic differences between carriers of the same translocations. In conclusion, we suggest that NGS-based methods, such as WG-MPS, can be successfully used for detailed mapping of translocation breakpoints, which can also be used in routine clinical investigation of ABT cases. Unlike de novo translocations, no associations were determined here between familial two-way ABTs and the phenotype of the affected members, in which the presence of cryptic imbalances and complex chromosomal rearrangements has been excluded. Future whole-exome or whole-genome sequencing will potentially reveal unidentified mutations in the patients underlying the discordant phenotypes within each family. In addition, larger studies are needed to determine the exact percentage for phenotypic risk in families with ABTs.

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Section: Introductionmentioning

confidence: 99%

Accurate Breakpoint Mapping in Apparently Balanced Translocation Families with Discordant Phenotypes Using Whole Genome Mate-Pair Sequencing

et al. 2017

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“…Not only the number of mutations in different genes but already the state (homo-/heterozygous) of the allele can affect disease severity [30] and even define which disease is developed. For example BRCA2 may cause Fanconi aenemia in the homozygous state and familial breast and ovarian cancer in the heterozygous state [31].…”

Section: Discussionmentioning

confidence: 99%

EIF2AK4 mutation as “second hit” in hereditary pulmonary arterial hypertension

et al. 2016

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BackgroundMutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene have recently been identified in recessively inherited veno-occlusive disease. In this study we assessed if EIF2AK4 mutations occur also in a family with autosomal dominantly inherited pulmonary arterial hypertension (HPAH) and incomplete penetrance of bone morphogenic protein receptor 2 (BMPR2) mutations.MethodsClinical examinations in a family with 10 members included physical examination, electrocardiogram, (stress)-echocardiography and lung function. Manifest PAH was confirmed by right heart catheterisation in three affected subjects. Genetic analysis was performed using a new PAH-specific gene panel analysis with next generation sequencing of all known PAH and further candidate genes. Identified variants were confirmed by Sanger sequencing.ResultsAll living family members with manifest HPAH carried two pathogenic heterozygous mutations: a frame shift mutation in the BMPR2 gene and a novel splice site mutation in the EIF2AK4 gene. Two family members who carried the BMPR2 mutation only did not develop manifest HPAH.ConclusionsThis is the first study suggesting that EIF2AK4 can also contribute to autosomal dominantly inherited HPAH. Up to now it has only been identified in a recessive form of HPAH. Only those family members with a co-occurrence of two mutations developed manifest HPAH. Thus, the EIF2AK4 and BMRPR2 mutations support the “second hit” hypothesis explaining the variable penetrance of HPAH in this family. Hence, the assessment of all known PAH genes in families with a known mutation might assist in predictions about the clinical manifestation in so far non-affected mutation carriers.

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“…Given the apparent influence of stress on phenotypically similar conditions in other species, it was speculated that these unafflicted males and females that carried this specific allele might not have experienced adequate levels of stress to manifest the WCS condition post slaughter. This ambiguity may be the result of incomplete penetrance (Zlotogora, 2003;Shawky, 2014). Incomplete penetrance affecting the expression of PSS has previously been observed in pigs (Ollivier et al, 1975;Smith & Bampton, 1978).…”

Section: Tablementioning

confidence: 90%

Identification of genomic regions that contribute to wet carcass syndrome in sheep

Westhuizen¹,

MacNeil²,

Scholtz³

et al. 2019

SA J. An. Sci.

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Wet carcass syndrome (WCS), which is observed predominantly in sheep, affects carcass quality negatively. After slaughter the carcass appears to be 'wet' with a subcutaneous accumulation of watery fluid. Not all animals in a contemporary group are afflicted, and experimental attempts to induce WCS have been unsuccessful. The reported prevalence of WCS in Dorper and Dorper crosses gave rise to the hypothesis that it may have a genetic basis. Therefore, the primary objective of this investigation was to test this hypothesis using a high-density SNP assay to search loci that may predispose sheep to WCS. Muscle samples from 43 afflicted and 41 unafflicted sheep were collected from slaughterhouses in the province of Northern Cape, South Africa, and in southern Namibia. Tests against candidate genes proved uninformative, as did runs of homozygosity. Potential associations between WCS and an autosomal genetic marker were investigated further in a case-control genome-wide association study. Separate analyses for each sex were motivated because single nucleotide polymorphisms (SNPs) on the X chromosome suggested quantitative trait loci. These analyses revealed significant associations between SNP and WCS in males, but not in females. Three SNPs that reached genome-wide significance in males are in strong linkage disequilibrium with the Duchenne muscular dystrophy, 5-hydroxytryptamine receptor 2C, and Teneurin transmembrane protein 1 genes. These genes are identified as positional candidate genes, and the Duchenne muscular dystrophy, 5-hydroxytryptamine receptor 2C genes have biological effects that have been documented in other species, making them plausible functional candidate genes for WCS in sheep.

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Reduced penetrance in human inherited disease

Cited by 38 publications

References 86 publications

Accurate Breakpoint Mapping in Apparently Balanced Translocation Families with Discordant Phenotypes Using Whole Genome Mate-Pair Sequencing

Accurate Breakpoint Mapping in Apparently Balanced Translocation Families with Discordant Phenotypes Using Whole Genome Mate-Pair Sequencing

EIF2AK4 mutation as “second hit” in hereditary pulmonary arterial hypertension

Identification of genomic regions that contribute to wet carcass syndrome in sheep

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