MG2024-05-Penetrance and expressivity.pdf

Complications of mendelian inheritance patterns Incomplete penetrance Variable expresivity Genotype-phenotype correlation Clinically useful to guide the diagnosis, prognosis and management of genetic disorders Utility hampered by heterogeneity in the phenotypic expression of a disease...

Complications of mendelian inheritance patterns Incomplete penetrance Variable expresivity Genotype-phenotype correlation Clinically useful to guide the diagnosis, prognosis and management of genetic disorders Utility hampered by heterogeneity in the phenotypic expression of a disease Variability in the clinical Variability in the genetic mechanisms presentation of a given genotype causing a given disease Penetrance and expressivity Genetic heterogeneity genotype phenotype Child affected by autosomal dominant disease born to unaffected parents. Why? Non paternity De novo mutations Incomplete penetrance Incomplete penetrance Penetrance: probability that a genotype manifests itself in a given phenotype (i.e., probability that the disease manifests in subjects with the causative genotype) Incomplete penetrance: some individuals with disease- causing genotype never develop any clinical signs or symptoms For disorders with dominant inheritance, may cause occasional skipping of generation(s) Fig 5.11 Strachan and Read. HMG5 Garland Example: split hand/foot malformation I (SHFM1) congenital limb malformation; absence of one or more fingers or toes (ectrodactyly); claw-like appearance and webbing penetrance 70% DLX5 gene - transcription factor important for bone development Image: https://boneandspine.com/ectrodactyly/  Variable expressivity Expressivity: degree to which a phenotype is expressed by a particular genotype. Variable expressivity: affected individuals within a pedigree show different degrees of severity or different features of the condition Example: Type 1 Waardenburg syndrome congenital hearing loss, pigment disturbances of iris, hair and skin mutations in PAX3 encoding a transcription factor important for embryogenesis Pedigree: affected family members show different features of syndrome despite having the same mutation in PAX3 Fig 5.10 Strachan and Read. HMG5 Garland Incomplete penetrance and variable expressivity Factors affecting penetrance and expressivity Physiological factors: age, sex, hormonal factors … Effect of age and sex on penetrance and expressivity Hemochromatosis abnormal accumulation of iron in parenchymal organs, leading to organ toxicity adult onset (age 40-60y in men, after menopause in women) increasing severity with age; variable expressivity between individuals with same genotype incomplete penentrance: lower in women (10%) than in men (30%) due to loss of iron via menstruation https://www.aafp.org/afp/2002/0301/p853.html Sex-limited phenotypes Defect is autosomally transmitted but is expressed in only one sex Familial male limited precocious puberty (FMPP) AD inheritance Affected boys develop secondary sexual characteristics in early childhood LHCGR gene, leutenizing hormone/choriogonadotropin receptor Gain-of function variant → increased levels of sex steroids in the context of low LH. In males → precocious testosterone production by Leydig cells In females → no effect due to the dual requirement of LH and FSH to promote Note: can be transmitted from father to son (hence not X-linked), and ovarian maturation. by healthy females who are non-penentrant carriers (hence not Y- linked) Factors affecting penetrance and expressivity Physiological factors: age, sex, hormonal factors … Genetic mechanisms repeat expansion (later lecture) mosaicism due to post-zygotic de novo mutation disease severity is typically lower in mosaic individuals than in those with a constitutive variant; depends on the degree of mosaicism and its tissue distribution genetic modifiers Genetic modifiers in mendelian diseases Genetic modifier: genetic variants that can modify the phenotypic outcome of the primary disease- causing variants Modifier variants: can increase or decrease the severity of the disease condition but are not disease- causing themselves (enhancer and suppressor variants), can change a target gene’s phenotype by having a genetic, biochemical, or functional interaction with one or more target gene(s), or gene product(s) → epistasis Rahit et al. Genes (Basel). 2020 Feb 25;11(3):239. may result in large phenotypic variability and changes in penetrance. Riordan et al. Am J Hum Genet. 2017 Aug 3;101(2):177-191. Factors affecting penetrance and expressivity Physiological factors: age, sex, hormonal factors … Genetic mechanisms repeat expansion mosaicism due to post-zygotic de novo mutation disease severity is typically lower in mosaic individuals than in those with a constitutive variant; depends on the degree of mosaicism and its tissue distribution genetic modifiers genetic compensation (genetic buffering): an organism with a pathogenic mutation does not develop the expected adverse phenotype due to compensatory actions of another gene or genes, which functionally compensate for the loss-of-function genotypes, restoring more normal physiological function. Epigenetic mechanisms: X chromosome inactivation, genomic imprinting, interindividual variability in epigenetic modifications and gene expression Environmental factors: diet, infections, smoking, medications, chemical pollutants … Glucose-6-phosphate dehydrogenase (G6PD) deficiency Inborn error of metabolism Most common hereditary enzyme defect - 400 million people worldwide; distribution similar to malaria X-linked recessive inheritance G6PD enzyme: participates in pentose phosphate pathway to generate NADPH critical role in RBCs to maintain levels of reduced glutathione (GSH), and hence, for detoxification of reactive oxygen species (ROS) Most subjects with G6PD deficiency are asymptomatic, but when exposed to oxidative stress may develop hemolytic anemia (low RBC count due to RBC destruction) Triggers for hemolytic anemia in G6PD deficiency Bacterial and viral infections e.g. malaria, pneumonia, hepatitis, HIV … Recht et al., 2014 https://www.who.int/publications/i/item/9789241506977 Fava beans and other legumes containing toxic alkaloid glycosides → Mediterranean G6PD deficiency (favism) Vicine Data mining of genome databases identifies healthy individuals with “pathogenic” genotypes for Mendelian disorders Chen et al., Nat Biotechnol. 2016 May;34(5):531-8 Tarailo-Graovac et al., Genet Med. 2017 Dec;19(12):1300-1308.  “Resilience Project” Aim: to identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders Bioinformatic analysis of existing genomic data from 12 cohorts worldwide genotyping array, WES or WGS data of 589,306 individuals 874 genes believed to cause 584 distinct severe Mendelian childhood disorders Chen et al., Nat Biotechnol. 2016 May;34(5):531-8 13 adults with variants for 8 severe Mendelian conditions, with no reported clinical manifestation of the indicated disease “… incomplete penetrance for Mendelian diseases is likely more common than previously believed” The identification of resilient individuals may provide a first step toward uncovering protective genetic variants that could help elucidate the mechanisms of Mendelian diseases and new therapeutic strategies. Chen et al., Nat Biotechnol. 2016 May;34(5):531-8 Note: only 2 out of 8 candidates identified are shown above; others are familial dysautonomia, epidermolysis bullosa simplex, Pfeiffer syndrome, autoimmune polyendocrinopathy syndrome, acampomelic campomelic dysplasia and atelosteogenesis Chen et al., Nat Biotechnol. 2016 May;34(5):531-8  Aim: to analyze the Exome Aggregation Consortium (ExAC) data set for the presence of individuals with pathogenic genotypes implicated in Mendelian pediatric disorders. Analysis of WES data on 60,706 unrelated individuals from 17 studies, excluding individuals with severe pediatric disease. 1,717 ExAC individuals (~2.8% of data set) with genotypes implicated in rare Mendelian disorders with variable phenotypic severity. 18 ExAC individuals with genotypes implicated in severe Mendelian early onset disorders with high Tarailo-Graovac et al., Genet Med. 2017 Dec;19(12):1300-1308. penetrance and low variability. (authors propose somatic mosaicism as possible explanation for some cases) … determining the prevalence of pathogenic genotypes in unselected populations… is crucial for understanding the penetrance of disease-associated variants, phenotypic variability, somatic mosaicism, as well as … for variant classification and predicted clinical outcomes. Reading Strachan and Read. Human Molecular Genetics Chapter 5 Patterns of inheritance Thompson and Thompson. Genetics in Medicine 7 Chapter 7 Patterns of single-gene inheritance