advanced exam 1, lecture 3

more factors that affect inheritance

Germline mutation

A gene change in the egg or sperm that becomes incorporated into the DNA of every cell in the body of the offspring

Somatic mutation

A gene change that occurs after conception, so the mutation is not observed in all cells; relevant to cancer and tumor testing

Gonadal mosaicism

When all or part of the gonadal tissue carries a mutation, arising from a new mutation during development of the ovary or testis

The mutated patch of gonadal tissue could be passed on, but there is no way to know how much of the gonad is affected or whether it will be transmitted. Increased recurrence risk to siblings, but can't say how much.

Why is there no specific recurrence risk for gonadal mosaicism?

The variant may be present in an entire ovary or testis but will not appear in lymphocytes, so blood tests are not useful

Why is germline (blood) testing ineffective for gonadal mosaicism?

The parent is usually unaffected but may have very mild features; mosaicism must always be considered when counseling for a "sporadic" condition

Clinical implication of gonadal mosaicism for an affected parent

A family appeared autosomal recessive but was actually autosomal dominant with mosaicism; blood tests proved paternity and neither parent carried the variant, so the conclusion was gonadal mosaicism in one parent

Osteogenesis imperfecta as an example of gonadal mosaicism

Because males have only one X chromosome

Why do genes on the X chromosome show unique inheritance patterns?

Deutan type is insensitivity to green light; protan type is insensitivity to red light

X-linked color blindness: deutan vs protan

Fabry's disease

X-linked; deficiency of galactosidase A causing heart and kidney disease and early death

G-6-PD deficiency

X-linked deficiency of glucose-6-phosphate dehydrogenase; severe anemic reaction after intake of primaquines in drugs and certain foods including fava beans

Hemophilia A is the classic clotting deficiency (factor VIII); Hemophilia B is Christmas disease, a deficiency of clotting factor IX

Hemophilia A vs Hemophilia B

Hunter syndrome

X-linked mucopolysaccharide storage disease from iduronate sulfatase deficiency; short stature, clawlike fingers, coarse facial features, slow mental deterioration, deafness

X-linked ichthyosis

Deficiency of steroid sulfatase enzyme causing scaly dry skin, particularly on the extremities

Lesch-Nyhan syndrome

X-linked deficiency of HPRT (hypoxanthine-guanine phosphoribosyltransferase) leading to motor and cognitive impairment, self-mutilation, and early death

Duchenne muscular dystrophy

Progressive, life-shortening muscle degeneration and weakness due to deficiency of the protein dystrophin

Human chromosome complement

23 pairs: 22 pairs of autosomes and 1 pair of sex chromosomes (XX or XY)

The presence of a Y chromosome activates development of male genitalia (45,X individuals develop with female genitalia (Turner syndrome))

What determines male development in humans?

Write the number of chromosomes, then the sex chromosomes, then details about any anomalies; 46,XX and 46,XY are typical complements

Cytogenetic notation format

The X has many expressed genes, so 46,XY individuals would have only 50% as much gene product without regulation; for autosomes, large extra or missing regions usually cause significant pathology

Why is X regulation necessary?

X-inactivation

One X chromosome in individuals with two X's is highly condensed and largely transcriptionally inactive; inactivation is random and occurs early in embryogenesis

Skewed X-inactivation

When one X is active in a significantly higher percentage of cells than the other; if the mutation is on the more-active X, the phenotype can be much more severe

Up to 15% of genes on the X chromosome escape inactivation even on the condensed chromosome

What fraction of X genes escape inactivation?

It may account for phenotypic findings in 45,X (Turner) and 47,XXY (Klinefelter) — in Turner, one X alone is fine, but the 15% of genes on the condensed X escape inactivation and produce a phenotype

Why does escape from X-inactivation matter clinically?

modifications from the mendelian dihybrid 9:3:3:1 ratio

what may reveal gene interactions when considering phenotype ratios?

One X is inactivated in each cell early in embryogenesis, and all cells of that lineage will have the same X inactivated

Why does X-inactivation produce clones?

Absence of sweat glands in patches in a carrier of anhidrotic ectodermal dysplasia

Clinical example of X-inactivation clonality

There is increased recognition that female carriers (people with two X chromosomes) can have a clinical phenotype

Why is dominant/recessive language falling out of use for X-linked conditions?

Due to skewed X-inactivation or, rarely, being homozygous (inheriting two affected X chromosomes, or a combination of inherited and de novo)

X-linked recessive: how can 46,XX individuals be affected?

Carrier mothers are typically unaware and must be referred to cardiology; phenotypes result from skewed X-inactivation and include muscle weakness, myalgia/cramps, left ventricular dilation, and dilated cardiomyopathy

Duchenne muscular dystrophy carrier phenotype

Usually unaffected, may have mild hyperuricemia; males have uncontrollable self-injury due to uric acid buildup

Lesch-Nyhan carrier phenotype

Ranges from asymptomatic to as severely affected as 46,XY individuals, with slightly reduced life expectancy (75.4 years vs 80 years)

Fabry disease carrier phenotype

X-linked dominant disorders

Occur in both 46,XY and 46,XX, with 46,XY more severely affected; sometimes lethal in 46,XY and therefore seen primarily in affected 46,XX individuals

Incontinentia pigmenti (often lethal in 46,XY), Coffin-Lowry syndrome, and X-linked hypophosphatemic rickets

Three examples of X-linked dominant disorders

Sex-limited inheritance

An autosomal trait seen exclusively in one sex, such as prostate or ovarian cancer

Sex-influenced inheritance

An autosomal trait seen more often in one sex, such as breast cancer or male-pattern baldness

Yes — Mendel's principle still applies, but the expected ratios will not be observed

Does independent assortment still apply when ratios are modified?

Blood type segregates 1:2:1 (codominance) and albinism segregates 3:1, giving a final ratio of 3:1:6:2:3:1

Modified 9:3:3:1 example: two AB-blood-type parents both heterozygous for albinism

The genes must assort independently (not linked), and each gene must produce distinct phenotypes with complete dominance

Two conditions required to analyze gene interactions from modified ratios

You need clearly distinguishable categories (black fur vs white fur), not quantitative gradations (dark gray vs light gray)

Why must traits be qualitatively different to assess gene interaction?

Epistasis

When one gene masks or modifies the effect of another gene at a different locus

Homozygous recessive at one locus blocks expression at other loci; one dominant allele affects expression at other loci; two gene pairs complement each other, requiring one dominant allele from each pair

Three forms epistatic interaction can take

The A locus controls agouti (A- gives yellow bands on black hair) vs nonagouti black (aa); the B locus is involved in pigment synthesis

Recessive epistasis in mouse coat color: the two loci

Pigment synthesis is necessary before black vs agouti patterning can be seen; one B allele allows pigmentation, but bb blocks pigment entirely

Why does bb produce albino mice regardless of agouti genotype?

9:4:3 agouti:albino:black — 9/16 A-B- agouti, 3/16 A-bb albino, 3/16 aaB- black, 1/16 aabb albino

F2 ratio from AaBb x AaBb in mouse coat color epistasis

Bombay phenotype

Recessive epistasis in humans: a recessive variant in FUT1 prevents synthesis of the complete H substance, so no sugar can be added and the person appears type O regardless of ABO genotype

A person can be genetically type A, B, or AB but phenotypically O, which can produce apparently impossible blood-type inheritance and implications for family dynamics

Why is the Bombay phenotype significant clinically?

About 1/10,000 in India, where it was originally found; about 1/million in Western Europeans

Bombay phenotype frequency

Multifactorial (complex) traits

Traits that run in families but do not follow strict Mendelian inheritance, resulting from multiple genes, environmental effects, and chance

Family members share a greater proportion of their genetic information and environmental exposures than random individuals in the general population

Why do multifactorial traits cluster in families?

Continuous (quantitative) multifactorial traits

Traits measured on a scale, such as height, weight, and blood pressure

Discrete (qualitative) multifactorial traits

Present-or-absent traits, such as congenital heart defects and cleft lip/palate

It can be genetic, or it can be due to shared environmental factors such as diet, socioeconomic status, and exposures

Two explanations for a cluster of affected individuals

When the disease is more common in the general population

When is a familial cluster more likely to be non-genetic?

Lambda-r (relative risk ratio)

The prevalence of disease in relatives of an affected person divided by the prevalence in the general population

If it equals 1, a relative has the same risk as the general population; greater than 1 means those with affected family members are at higher risk

How to interpret lambda-r

To estimate the heritability of a multifactorial trait

Purpose of twin studies

The trait is determined by genetic and nongenetic risk factors; individual factors have small effects but together can have large effects; risk factors interact with environment to produce phenotype

Three assumptions of the liability/threshold model

Liability is plotted on the x-axis as a bell curve in the normal population; those in the tail have high liability

Liability model for continuous traits

The same bell curve, but with a threshold: those in the tail above threshold are affected, and those below it are unaffected even with fairly high liability

Liability model for discrete traits

Family members cluster on the liability axis, effectively shifting the threshold lower — "shifted risk" — so siblings and children of an affected person have increased risk

How does the liability curve change for families of an affected person?

If a condition is more common in males and a female is affected, recurrence risk for relatives of affected females is higher than for relatives of affected males

Influence of sex on recurrence risk

A male first-degree relative of an affected female — high liability in the family combined with a lower threshold for males

Greatest recurrence risk scenario in a sex-influenced multifactorial condition - one that occurs more often in men

A more severely affected individual likely has higher genetic liability, so risk to relatives is higher

How does severity affect recurrence risk?

More affected first-degree relatives means higher liability in the family and higher risk

How does the number of affected relatives affect risk?

Most affected children have unaffected parents, and the condition is not necessarily seen in every generation

Two pedigree hallmarks of multifactorial inheritance

Familial aggregation patterns do not conform perfectly to multifactorial expectations, so risk is based on information gathered through observation, experimentation, and research

Why use empiric data in clinic for multifactorial risk?

"Many to one"; Allelic and locus heterogeneity

different genetic causes lead to the same phenotype

"One to many"; Pleiotropy

a single genetic cause leads to multiple phenotypes

Allelic heterogeneity

When different variants in the same locus/gene produce the same or similar phenotype

Over 1000 known different pathogenic variants in CFTR cause CF; severity may vary but it is the same disease

Cystic fibrosis as allelic heterogeneity

Locus heterogeneity

When variants in different loci/genes independently produce the same disease or genetic condition

Degeneration of photoreceptors leading to blindness, caused by mutations in over 100 genes: 5-15% X-linked, 15-25% AD, 5-20% AR, 40-50% unknown

Retinitis pigmentosa as locus heterogeneity

Mutations in more than 150 genes, including at least 7 X-linked forms, 63 AD forms, 86 AR forms, and 9 mitochondrial forms

Nonsyndromic hearing loss as locus heterogeneity

No — locus heterogeneity means the genes and causes are unknown, so no definitive chance can be given

Can two deaf parents be given a definitive risk without genetic testing?

Pleiotropy

A single gene whose product affects multiple, often unrelated, phenotypic traits or organ systems

Variants in lamin A/C affect striated muscle, cardiac muscle, adipose tissue, peripheral nerve, bone, and skin

LMNA as an example of pleiotropy

Phenotypic heterogeneity

When the same gene produces distinct clinical presentations across individuals; helps explain incomplete penetrance and variable expressivity

Cardiac (conduction defects, dilated cardiomyopathy), neuromuscular (Emery-Dreifuss MD, Charcot-Marie-Tooth type 2), fat/metabolic (familial partial lipodystrophy), and premature aging (Hutchinson-Gilford progeria)

Four categories of LMNA-related disease

About 5% in the US, derived partly from early linkage analysis studies; among groups seeking paternity testing in 2022 using FamilyTreeDNA the rate was 11%

Misattributed paternity estimates

About 50,000 children per year in the US, though the figure is probably unreliable since there are no registries or tracking

Donor gamete conception estimates

All cells have mitochondria, all mitochondria have their own DNA, and all mitochondria are derived from those in the egg

Mitochondrial inheritance: core principle

All eggs from a person with a mitochondrial disease are at risk of resulting in a child with mitochondrial disease

Recurrence implication of mitochondrial inheritance