Genetics Flipped Lesson 9.PDF

MD210 Genetics Flipped Lecture 9 – Cystic Fibrosis and Population Screening Puzzle - Why do some communities/ethnic groups have different risk of inherited genetic disorders than the general population? - Founder Effect - reduction in genetic variation due to migration/isolation of a small number of...

MD210 Genetics Flipped Lecture 9 – Cystic Fibrosis and Population Screening Puzzle - Why do some communities/ethnic groups have different risk of inherited genetic disorders than the general population? - Founder Effect - reduction in genetic variation due to migration/isolation of a small number of endogamous individuals from a large population Groups That Practice Extensive Endogamy - “marriage” within a specific community - May be a conscious choice to preserve cultural/religious identity - May be choice related to perceived superior social status (Royal Families of Europe) - May be related to social exclusion/caste so that intermarriage is prohibited - In parts of India “Dalit” (official term “Scheduled Castes”) - Japan (“Buraku”) - Nearer to home – some Irish travellers Founder Effect Example - Pennsylvania Amish & Ellis van Creveld Syndrome - Ellis van Creveld: short stature, polydactyly, abnormality of nails and dentition, cardiac defects - Allele frequency 7% Pennsylvania Amish and 0.1% in General Northern European Population - EVC Gene Short Arm of Chromosome 4 The Amish Founder Effect - Relatively discrete breeding sub-population (endogamy) - Derived from a small group of related people (founders) - If a specific mutation was present by chance in the founders it may be disproportionately common in the expanded group derived from that population - Likewise frequent disease associated alleles that are by chance missing in the founders may be disproportionally uncommon in the expanded group derived from that population - Exogamy (marrying unrelated people) will tend to dilute or diminish founder effect Founder Effect and Genetic Drift Fanconi Aplastic Anaemia - FA is a rare genetic syndrome characterized by short stature, various congenital abnormalities, bone marrow failure, and cancer predisposition - Autosomal recessive - Heterozygotes may have short stature, but no bone marrow aplasia or increased cancer risk* - At least 15 genetic variants associated with distinct disease profiles. - 3 important ones: o FANCA Chr 16 o FANCC Chr 9q o FANCG Chr 9p Fanconi Anaemia - FA pathway is responsible for fixing DNA damage during DNA replication - Quick dividing cells most affected – bone marrow, foetal - Predisposition to Malignancy in surviving cells - About 20% homozygotes develop cancer - Median age of onset 16 - Haematological malignancy (AML, MDS, ALL) - Squamous cell cancers - Hepatomas Fanconi Anaemia - Overall prevalence of 1 to 5 per million - Carrier frequency of 1 in 200 to 1 in 300 Founder effects – carrier frequency: - Afrikaner population of South Africa 1 / 77 - Ashkenazi Jewish 1 / 89 - Spanish Gypsies 1 in 64 to 1 in 70 Nearer to home: Some Irish Travelers have increased frequency Ashkenazi Jews - Middle Ages- Jews Living Along the River Rhine - Subsequently centred in Poland and Lithuania - Distinctive customs from Sephardic Jews (little intermarriage – with Sephardic Jews or nonJews) - Recovered from a genetic bottleneck of ~400 families (circa year 1000) (only around 400 families remained and because they were endogamous this led to a decrease in genetic diversity) - Migration to US from late 17th/early 18th century - Relatively small initial population (founders) Ashkenazi Jews - Current Ashkenazi Jewish population in the US (6-7 million) derived from a limited number of people with extensive intermarriage - Relatively high incidence of a number of inherited genetic diseases: (and lower incidence of some other genetic diseases) Cystic Fibrosis (carrier 1/24) Tay-Sachs Disease (carrier 1/25) Canavan Disease (carrier 1/40) Niemann-Pick Disease – Type A (1/90) Gaucher Disease – Type 1 (1/14) Familial Dysautonomia (FD) (1/30) Bloom Syndrome (1/100) Fanconi anaemia – Type C (1/89) Mucolipidosis IV (ML IV) Tay Sachs Carrier Screening - Carrier screening: testing a target population to identify unaffected carriers of a disease allele - Fatal disease in homozygotes - Deficiency in lysosomal enzyme β-hexosaminidase A (HEX A) - substrate GM2 ganglioside accumulates - Blindness, seizures, hypotonia - Death by 5 years - Carrier screening in N. America - Education on risks, testing and reproductive options - 90% reduction in Tay-Sachs disease births between 1970s1990s - 0% by 2003 Principles of Population Screening Each screening programme needs to be appraised for viability, effectiveness and appropriateness in each target population National Screening Committee UK international criteria: - The condition – serious, well understood and relatively common (cost/benefit) - The test – acceptable, easy and cheap, valid and reliable - The intervention – effective treatment/counselling, prenatal diagnosis and ART available - The screening programme –effective (clinical data), ethical, benefit outweighs harms - Implementation criteria – accessibility, resources for diagnosis and treatment, communication of results, data privacy, quality assurance Cystic Fibrosis - CFTR Gene - Cystic Fibrosis Transmembrane Regulator - Ion Channel (Cl- and HCO3-) - Chr 7q31.2 (locus) - 27 Exons & 230 000 base pairs - 12 Transmembrane domains - 2 nucleotide binding domains - 1 regulatory domain - Function: “Gating” - ATP dependent cycling between conducting ions (open) and not conducting ions (closed) Cystic Fibrosis Manifestations – Viscous Secretions - Sweat (Na+ >60 mmol/L) - Lungs – thick sticky mucus, infections - GIT (may present with obstruction in infancy – meconium ileus) - Frequent greasy, bulky stools (steatorrhea) - Sinuses - polyps, thick sticky mucus, infections - Pancreas (malabsorption, failure to thrive, CF) - Male infertility – CBAVD (95% of males and 20% females infertile) Respiratory Mucosa – Normal vs CF Cystic Fibrosis Mutations - Hypomorphic (less function) heterogeneity: thousands of alleles associated with disease are known - Loss of function mutations tend to be more heterogeneous than gain of function mutations - Recessive pattern of inheritance (affected people usually have unaffected parents) - CFTR has biallelic expression - limited/no clinical effect in heterozygote as CFTR protein is haplosufficient Abnormal CFTR Alleles - Abnormal allele in 1/25 of Northern Europeans [1/500 Asians] - Carrier rate in Ireland 1 in 19 - Most common is p.F508del (a.k.a. Delta-F508, ΔF508, DF508) - 70% of CF alleles in Northern Europeans - Deletion of phenylalanine at position 508 in CFTR (in NBD-1) - Altered CFTR protein is degraded intracellularly and does not make it to the apical cell membrane (loss of function) - ΔF508 = Frameshift mutation - Deletion of 3 Nucleotides in Exon 10 - ATC-ATC-TTT-GGT-GTT (wt) - Ile Ile Phe Gly Val - ATC-ATT-GGT-GTT (CF) - Ile Ile Gly Val Mutations in CFTR Gene The frequency of DeltaF508 Depends on Geography - 88% of abnormal alleles in Denmark are DF508 - 50% in Italy - About 30% in Turkey Why is this allele so common ? - Hypothesis: heterozygote advantage (protected against dehydration due to diarrhea – cholera, typhoid fever epidemics) Is Screening Available for Cystic Fibrosis? - Individuals / Couples could be tested to determine if heterozygous (Aa) with a view to planning pregnancy - Testing of embryos for purposes of embryo selection - Prenatal testing on amniotic fluid with a view to termination of pregnancy - Screening of newborns to provide early detection and intervention - The challenge is > 2000 mutations - Easier way to test – blood spot test – blood level of immuno reactive tripsinogen IRT - 99% effective Things to Remember 1. A discrete population for purposes of genetics is defined in terms of mating not geography 2. Founder Effect can result in a high frequency of a specific allele variant in a specific population (e.g Fanconis anaemia in Spanish Gypsies, Tay-Sachs disease in Ashkenazi Jews) 3. Population screening has important ethical considerations and any new screening programme must be appraised for its suitability in each target population 4. Something that is a useful diagnostic test is not necessarily a good population screening test 5. Cystic fibrosis is an autosomal recessive condition common in people of northern European extraction 6. Frame Shift Mutation refers to a mutation that puts the trinucleotide sequences that code for an amino acid out of order Question: An endogamous Ashkenazi Jewish population in America have an increased frequency of a mutated allele for FANCC relative to the general population. Which of the following statements is most appropriate? - It is likely that the practice of endogamy by the Ashkenazi Jews was the only cause for this increased frequency - The frequency of this allele in the general population will likely change more than in the Ashekanzi Jews as a result of genetic drift - It is likely that the founder population of immigrating Ashkenazi Jews had a higher frequency of this mutation than the general population ?? - Around 50% of homozygotes for this mutation will develop cancer