MEDGEN403 Module 2: Genes & Genomes Lecture 1 PDF

MEDGEN403 Module 2:Genes&Genomes Lecture 1: Single Gene does not equal Simple Dr. Oana Caluseriu, MD, FRCPC, FCCMG September 25, 2024 Medical geneticist and Associate Professor Objectives 1. Describe the approach to assessing rare genetic disease 2. Def...

MEDGEN403 Module 2:Genes&Genomes Lecture 1: Single Gene does not equal Simple Dr. Oana Caluseriu, MD, FRCPC, FCCMG September 25, 2024 Medical geneticist and Associate Professor Objectives 1. Describe the approach to assessing rare genetic disease 2. Define the phenomena of reduced penetrance, variable expressivity, sex effects, de novo variation, pleiotropy, and digenic and polygenic effect 3. Describe how the above phenomenon impacts our understanding of typical modes of inheritance  DNA 3 billion letters Coding region 20 000 genes 1.5% a deal w mendelliongenetics inclinical which is codingregions Recent history of the DNA NGS 2010 nos 2005 microarray Earyotype 2001 CDNAseq diattofhuman 1977 genome incomplete sangerseq 1956 1953 Moore’s law  KARYOTYPE = 5-10 Mb 5-10 % = 10-15 % ouing intricatedetails COMPARATIVE GENOMIC HYBRIDIZATION 100 kb diseaseassocwone prevthoug notio s gene but ~80% = 1bp A/G ofmandgenedisord haveagentic 0-100% ifordered s  Next Generation Sequencing (NGS) TARGETED allgenesinnownassocw 20 genome y genesknownresponsible PANELS (group of genes) C WES: Whole EXOME sequencing (protein coding) C- 1-2% DNA no classofdiagnosis WESdoesnothavehypothesis an codingregion Non-TARGETED WGS: WHOLE GENOME SEQUENCING R/C- 100% DNA  DNA= 3 billion bases 99.9% identical between any two individuals in the world 2-3 million polymorphisms 0.1.1difference in any2human mtane ushavediffheightweight I 2 3million etc normal notfordisorder 500 rare missense ~ 20 homozygous, ~ 20 rare ~ 50 reported variants disease-causing mutations ~100 ~ 100 rare variants in known disease genes 1-2 de novo protein inherited LOF variants coding mutations ancarryvariants predispos Unknown number of sequencing errors We are all mutants PATHOGENIC BENIGN  Molecular basis known for a described phenotype 1953-2012 2012-2024 3674 7547 morethan2xmore 253geneticdisdiscovered yr As of September 20, 2024 SINGLE GENE DISORDER  Susceptibility to complex diseases and infection (As of September 20, 2024) PHENOTYPE GENES 671 501 PHENOTYPE GENOTYPE MENDELIAN DISORDERS Down syndrome Trisomy 21 MULTIFACTORIAL High blood pressure INHERITANCE Genes Environment complex  Why do we test? CLINICAL HETEROGENEITY complicates GENETIC HETEROGENEITY INCOMPLETE PENETRANCE  Terminology Allele alternate forms or variants of a particular gene most basic classification would be normal and mutant Heterozygous two different alleles at specific locus for recessive alleles – heterozygote = a carrier Homozygous Presence of the same alleles at a locus Usually both normal or both mutant Hemizygous only one copy of an allele is present  Single Gene Disorders Dominant The heterozygote will manifest the variant phenotype Recessive Only the homozygote (or for X-linked disorders – hemizygote ie male) expresses the variant phenotype The heterozygote is healthy and called a carrier  Autosomal Dominant VERTICAL Both males and females are affected Affected individuals usually have an affected parent Male to male transmission 50% risks  Autosomal Dominant Obligate carrier Penetrance with normal Yes or No phenotype Incomplete penetrance means some heterozygotes will have a normal phenotype Expressivity Range or degree Variable expressivity implies that the phenotype can vary 1 from individual to individual Variable severity between sibs with same gene Variable clinical Expressivity justwoning selfexplanatory off everyonepresents Saethre-Chotzen Syndrome TWIST1 mutations  Incomplete Penetrance Treacher Collins Syndrome TCOF1 gene AD severefacialphenotype  Regulatory variants as modifiers of coding variant penetrance Paper Readthe Castel et al, 2018 De Novo Mutations Dom mostcommoncause ofgeneticdisorder New mutation in germ cell New (de novo) mutation occurs in germ cell of parent hard b c we do blood No family history of dominant disorder 50% chance of affected individual passing Affected offspring condition on Most common cause of genetic disorders  Tuberous sclerosis Risk of recurrence for a couple with a child with a known new mutation which neither parent carries is that for Germinal Mosaicism MOSAICISM a challenging concept in biology and medicine singlegene w diffmutations thatresults in a diffplaces diff disorder PLEIOTROPY the production by a single gene of two or more apparently unrelated effects (Oxford dictionary) Distribution of Phenotypes across Genes (Updated September 19th, 2022) Number of genes 3453 with 1 phenotype Number of genes 897 with 2 phenotypes Number of genes 328 with 3 phenotypes Number of genes 251 with 4+ phenotypes FGFR3 Achondroplasia Hypochondroplasia Lacrimo-auriculo-dento-digital syndrome Thanatophoric dysplasia Crouzon syndrome with Acanthosis nigricans Muenke syndrome Autosomal Recessive HORIZONTAL Males and females affected Parents are not affected On average ¼ are affected Consanguinity increases the risk  Autosomal Recessive - Consanguinity Proportion of genes shared increases the chance that both parents are carriers (shared genes identical by descent) First Parent child/ ½ degree sibs incest Second Aunt/uncle 1/4 carries up to a 50% risk degree niece/nephew 1st cousins Third First cousins 1/8 about 2% increase in risk degree 2nd cousins Fourth Second cousins 1/32 no increased risk degree 1  Primary Ciliary Dyskinesia (PCD) aneltest Gene Symbol 1 / Locus Name % of All PCD Mutations Detected 2 Test Availability cilia cells affected 3 DNAI1 / CILD1 2%-9% Clinical DNAAF3 / CILD2 Unknown 6 Sequence Clinical Alungdisorders variants 5 DNAH5 / CILD3 15%-21% 7 Clinical Exonic or whole- gene deletions 10 Sequence variants 5 DNAAF1 (LRRC50) / CILD13 4%-5% 11 Clinical Exonic or whole- gene deletions 12 NME8 (TXNDC3) / CILD6 Unknown 13 Clinical 14 DNAH11 / CILD7 6% Clinical DNAI2 / CILD9 2% 15 Clinical DNAAF2 (C14orf104, KTU,