Human Pedigree

what is a pedigree

a diagram of a family showing relationships and phenotypes

what is a monogenic disease

disease caused by variants in a single gene

why do pedigrees matter

Mendelian characters are recognised by the characteristic pedigree patterns they give and the mode of inheritance deduced is the basis of the risk estimates used in genetic counselling

BUT with small human families the mode of inheritance can rarely be defined unambiguously from a single pedigree

what pattern do monogenic diseases follow

Mendelian patterns:

• very high penetrance

• minimal environment influence

• individually rare but each has a large effect

(there are > 10,000 monogenic traits)

what is pathogenic variant

a sequence change that causes diseas

what is penetrance

proportion of people with a disease genotype who show the phenotype

how are Mendelian disorder conventionally classes as

• autosomal dominant/recessive

• X-linked dominant/recessive

• mitochondrial dominant/recessive

examples of autosomal recessive diseases

• phenylketonuria (PAH gene)

• cystic fibrosis (CFTR gene)

• sickle-cell anaemia (HBB gene)

• oculocutaneous albinism type II (OCA2 gene)

examples of autosomal dominant diseases

• Huntington disease (HTT)

  • a CAG repeat disorder, normal alleles carry 6-34 repeats, pathogenic alleles 36-100+

• myotonic dystrophy 1 (DMPK)

  • a CTG expansion in the 3’ untranslated region, normal 5-37 pathogenic 50-10000

• familial hypercholesterolaemia (LDLR, APOB genes)

• neurofibromatosis 1 (NF1 gene)

• polycystic kidney disease ½ (PKD1, PKD2 genes)

examples of X-linked recessive diseases

• haemophilia A (F8 gene)

• Duchenne muscular dystrophy (DMD gene)

  • Duchenne and Becker dystrophy are two clinical outcomes of mutations in the same gene, complete inactivation gives the severe Duchenne form, partial the milder Becker form

examples of X-linked dominant diseases

• X-linked hypophosphataemic rickets (PHEX gene)

• Rett syndrome (MECP2)

  • in males is usually lethal before birth

what is meant by the term polygenic

many genes of small effect

what is the first Mendelian trait documented in humans

Brachydactyly - shortness of fingers and toes

type A1 is autosomal dominant (Indian Hedgehog IHH gene)

homozygotes are more severly affected

molecular reason for dominance

alleles are dominant when a cell with one working copy of the allele cannot meet demand (haploinsufficiency) or when mutant product intereferes with the normal product (dominant-negative effect)

features of dominant pedigrees

• does not skip generations (vertical transmission)

• affected individuals have an affected parent (exception: non-penetrance and new mutation)

• one allele suffices (Aa or AA)

• 50% risk to a child of an Aa x aa mating

• males and females affected equally

• transmitted by either male or female (male to male transmission occurs which separates AD from X-linked inheritance)

autosomal diseases are rare so matings between 2 affected individuals are uncommon (most are Aa x aa therefore the usual risk is 50% and does not skip generations)

AA individuals are only seen in rare Aa x Aa matings

give 2 explanations as to how a parent can be unaffected to an affected child in an AD family

1) reduced penetrance

2) de novo mutation

features of Huntington disease

• age-dependant penetrance - symptoms begin after the age of onset (about 40 years old) so many individuals have children before they know they carry the allele

• Venezuela HD project studies the world’s largest family around Lake Maracaibo with the highest known concentration of Huntingtons disease

  • original progenitor of the family lived in the early 1800s and descendants number >18,000 (many affected or at risk)

• the Venezuelan pedigrees allowed mapping of the HD gene to chromosome 4, HTT has an expanded CAG repeat (>35) with anticipation (earlier onset in later generations especially through paternal transmission)

what is meant by the term anticipation

the tendency for a condition to become more severe or begin earlier in successive generations

what is meant by the term founder effect

a population derived from a small number of founders, one of whom carry the gene

why are carriers usually unaffected in autosomal recessive diseases

one functional allele provides enough product (haplosufficiency)

what do autosomal recessive diseases require

two copies of the recessive allele

features of autosomal recessive diseases

• affected individuals are usually born to unaffected parents who are asymptomatic carriers

• either sex is affected

• assuming both parents are phenotypically normal carriers there is a 25% chance of them having an affected individual

• trait skips generations

• trait may appear in consecutive generations if parent mating is affected x carrier (quasidominance/pseudodominance, can be mistaken for autosomal dominant, clues that its recessive: trait is rare, affected spouse is related (consanguinity), population has a high carrier frequency)

describe complementation

• all children of 2 affected parents are affected is only true if both parents are homozygous for mutations at the same locus

• if 2 people with congenital hearing loss marry the children usually have normal hearing if the parental mutations are in different genes (aaBB x AAbb), all children are double heterozygotes (AaBb) and since both conditions are recessive they hear normally

  • Usher syndrome (recessive hearing loss plus retinitis pigmentosa) can be caused by mutations at 10 or more unlinked loci

factors that complicate pedigree patterns

1. a common recessive condition mimicking a dominant pedigree

2. non penetrance

3. variable expression

4. imprinting

5. male lethality in X-linked dominant conditions

6. inbreeding in X-linked recessive pedigrees

7. new mutations and mosaicism

what is meant by reduced (incomplete) penetrance

individuals with a disease-causing genotype do not develop the phenotype but can transmit the allele

(in an autosomal dominant pedigree this appears as a skipped generation)

how to calculate penetrance

penetrance (%) = people with the genotype who show the phenotype/all people with the genotype

(breast cancer risk is about 70% by age 80)

an unusual genetic background, particular lifestyle or chance can prevent the phenotype from appearing

why some diseases have age dependant penetrance

slow accumulation of a noxious substance, incremental tissue death, inability to repair some sort of environmental damage

what is meant by the term expressivity

severity/range of the phenotype among those who show it

(penetrance is all or none but severity can vary, other genes, environmental factors or pure chance can influence the development of the symptoms)

what conditions are non-penetrance and variable expression typically problems of

dominant conditions as non-penetrant cases are hard to spot in recessive pedigrees and as a general rule recessive conditions are less variable probably because as a heterozygote’s phenotype balances two alleles and is therefore more sensitive to outside influence

describe the CFTR gene

• unusually large, 27 exons, around 190kb

• chromosome 7q31

(modifier genes do not cause the disease but alter its severity)

describe the mutations in CFTR

• mutations disrupt the chloride ion channel in cell of the pancreas, lung and other tissues

• manifestations: fibrotic lesions in the pancreas, intestinal involvement (meconium ileus, malabsorption), pulmonary disease - inflammation and bronchial infection leading to end-stage fibrotic lung disease

• which organ is affected the most varies between patients

(p.F508del is the commonest mutation in all European populations and probably of ancient origin)

what is meant by the term compound heterozygote

carries two different pathogenic alleles at one locus

what is meant by a nonsense mutation

premature stop

distinguish allelic from locus heterogeneity

allelic: many variants within one gene

locus: variants in different genes giving the same phenotype

what CF-causing varriants tend to produce more severe diseases

the variants that give complete absence of chloride channels at the cell surface

how is the variation in lung-disease severity among patients with identical CFTR genotypes explained

it is explained by the modifier gene TGFB1 whose increased expression is associated with obstructive pulmonary disease

(identifying modifier gene in humans is extremely challenging as humans show greater genetic diversity and a wider variety of environments than lab animals)

what is meant by the term modifier gene

a different gene that alters the effect of the disease gene

not the same as allelic heterogeneity (different variants of the disease gene) or locus heterogeneity (different genes that can each cause the disease)

what is meant by the term pleiotropy

one gene gives rise to multiple phenotypes

describe pleiotropy using Marfan syndrome as an example

• FBN1 gene, fibrillin-1, an extracellular component expressed in many tissues, autosomal dominant, chromosome 5q

• tall elongated body, long limbs/fingers (arachnodactyly), less dislocation (eye), aortic root dilatation (heart)

• as different family members show different organ features a parent diagnosed by bad sight and long limbs may have a child whose main problem is the heart, so the inheritance is not obvious

how can twins be discordant

if the de novo mutation arises after the embryo splits or in one gamete

(most new point mutations arise in the male germline rate increases with father age eg around 80% of achondroplasia cases are de novo)

what is meant by the term germline mosaicism

a genetic condition where a person has a population of egg or sperm cells with a genetic variant or mutation, while the rest of the body's somatic cells (such as blood or skin cells) do not carry it

why does a fully penetrant lethal dominant condition always arise by fresh mutation

because affected people cannot reproduce

for non-lethal but deleterious dominant conditions the argument applies to a smaller degree

serious X-linked recessive diseases also show a significant proportion of fresh mutations

autosomal recessive pedigrees are not significantly affected

why are consanguineous unions more likely to produce offspring with AR disorders

because relatives share alleles inherited from a common ancestor

consanguineous marriages show higher mortality in most populations

why does consanguinity matter for rare autosomal recessive disease but little for common autosomal dominant disease

rare autosomal recessive alleles are unlikely to be shared by unrelated parents, relatives are far more likely to carry the same one, autosomal dominant disease needs only one allele

what is the coefficient of relationship

proportion of genes 2 people share by virtue of their relationship

first degree relatives (parents, children and full siblings) share one half

second degree (grandparents, uncles/aunts, half-siblings) share one quarter

third degree (first cousins) share one eighth

what is the coefficient of inbreeding (F)

the probability that they receive 2 alleles identical by descent at a a locus, it equals half the coefficient of relationship of the parents