advanced genetics exam 1 diseases and mechanisms

phenylketonuria (PKU)

loss of function; null allele causes more severe phenotype, requires severely restructed diet to avoid cognitive defects

oesteogenesis imperfecta type I

dominant loss of function; AD, caused by reduction in collagen biosynthesis

familial hypercholesterolemia

incomplete dominance; heterozygotes have elevated cholesterol levels, homozygotes have greatly elevated cholesterol levels, both at an increased risk of heart disease

bombay phenotype

recessive epistasis; recessive variant in FUT1 prevents synthesis of the complete H-substance, which means it cannot be modified with A or B antigens, could genotypically be type A, B, or AB, but phenotypically will be type O

achondroplasia

homozygous lethal; dominant phenotype seen in living heterozygotes, recessive phenotype is lethality → instead of a 3:1 phenotypic ratio in progeny where both parents are heterozygous, you see a 2:1 ratio, variant is in FGFR3 gene

osteogenesis imperfecta type II

dominant lethal; heterozygous state is lethal, affected individuals do not reproduce before dying, so all variants are de novo

breast cancer (BRCA1/2)

incomplete penetrance; not everyone with BRCA variant will develop breast cancer by a certain age

van der woude syndrome

incomplete penetrance; lip pits and cleft lip/palate

neurofibromatosis type I

variable expressivity, complete penetrance; all individuals who carry the variant will have some phenotypic changes if they receive a careful clinical exam

waardenburg syndrome

variable expressivity AND incomplete penetrance; AD, prevalence 1/42,000, prigmentary differences of eyes (bright blue, different colored), skin (hypopigmentation), and hair (white forelock); dystopia canthorum (eyes look far apart but are not)

turner syndrome

45, X → 1/200 to 1/2500 live born females; less than 1% of 45, X conceptions result in a live born child, although health of children is usually good

• associated with short stature, hypertension, elevated hepatic enzymes, primary ovarian insufficiency, cardiac anomalies, renal anomalies, and sensorineural hearing loss; cardiovascular risk is high, with higher-than-average mortality rates

• can result from nondisjunction in either parent

• 70-80% are due to fertilization with a sperm that lacks a sex chromosome

• unlike other aneuploidies, no link to advanced maternal or paternal age

• about 5% of females with TS have spontaneous pregnancies (most of these are mosaic individuals)

• pregnancy rates using IVF with donor oocyte is similar to the general population, but higher rates of miscarriage

klinefelter syndrome

47, XXY → 1/500 to 1/1000 live born males

duschenne muscular dystrophy

x-linked condition; 46, XX individuals may experience some manifestations due to skewed x-inactivation or rare homozygotes

mutations in DMD gene, produces dystrophin protein (duplications/deletions are out of frame)

becker muscular dystrophy

x-linked condition; mutations in DMD gene, produces dystrophin protein (duplications/deletions are in frame → reduce gene functions, but less severe)

lesch nyhan syndrome

x-linked; some carriers may have hyperuricemia (uric acid buildup in the blood causes self-injurous behaviors)

fabry disease

x-linked; carriers range from asymptomatic to being as severely affected as 46, XY individuals

incontinentia pigmenti

x-linked dominant; lethal in 46, XY individuals and therefore is primarily seen in 46, XX

coffin-lowry

x-linked dominant; difference in severity in 46, XY individuals and therefore is primarily seen in 46, XX

x-linked hypophophatemia rickets

x-linked dominant; difference in severity in 46, XY individuals and therefore is primarily seen in 46, XX

prostate cancer

sex limited; a female could still inherit the variant that increases their risk, but wouldn’t affect them (could still be inherited)

breast cancer

sex influenced; more often seen in females, but could still occur in males

open neural tube defects and hip dysplasia

discrete traits; more common in females

congenital diaphragmatic hernia, hirschspring disease, and cleft lip/palate

discrete traits; more common in males → shifts threshold for males to the left; if female is affected, family as a whole will have a hgiher liability; greatest recurrence risk would be a male first degree relative of an affected male (high liability in family, lower threshold for males)

cystic fibrosis

allelic heterogeneity; over 1,000 known different pathogenic variants across the CFTR gene (severity varies, same disease)

retinitis pigmentosa

locus heterogeneity; can be caused by mutations in over 100 genes

non-syndromic hearing loss

locus heterogeneity; can be caused by mutations in over 150 genes; at least 7 x-linked, 63 AD, 86 AR, and 9 mitochondrial; recurrence risk ranges from 0% to 100%

LMNA-related conditions (laminopathies)

pleiotropy and phenotypic heterogeneity; variants in lamin A/C affect striated muscle, cardiac muscle, adipose peripheral nerve, bone, and skin

• premature aging syndromes

• neuromuscular diseases

• cardiac conditions

• fat/metabolism disorders

cornelia de lange syndrome

cohesinopathy; 60% of cases from NIPBL (AD); 5-7% from HDAC8 (XL), RAD21 (AD), SMC1 (XL), SMC3 (AD)

most cases are de novo; rare familial cases due to germline mosaicism or transmission from mildly affected parent

• Synophrys, long lashes, anteverted nares

• Growth restriction and limb reduction defects

• Hirsutism

• Intellectual disabilities/delays/behavior differences

• Variable: GI, heart defects, hearing loss → pleiotropy

retinoblastoma

loss of function; RB1 variants act as AD cancer susceptibility syndrome (cancer risk gene); can be inherited or de novo; bilateral is very likely associated with germline variant and is usually diagnosed earlier, 15% of unilateral disease is associated with germline variant, individuals with germline variants have an increased risk of forming other tumors (not seen in individuals with sporadic)

trisomy 13, trisomy 21, trisomy 18, klinefelter syndrome, and trisomy x

aneuploidies associated with advanced maternal age

turner syndrome and jacob’s syndrome (47, XYY)

aneuploidies that are maternal-age independent

down syndrome

47, X_ +21 → most common chromose disorder in live born children (~1/700); variable phenotype due to mosaicism; characteristic facial features and increased risk for some health concerns:

• congenital heart defects

• hearing and vision differences

• hypothyroidism

• leukemia

• mild to moderate ID

• early onset Alzheimer’s

trisomy 18

47, X_ +18 → 1/5000 live births; increased risk for congenital heart defects, kidney malformations, omphalocele, severe intellectual disability, and poor growth

• clenched fists with overlapping fingers and clubbed or rocker-bottom feet

• most do not survive to term, and of that those do, most don’t survive past 1 year

again, mosaicism can cause variable symptoms, but we can only know mosaicism levels in the blood; not in other tissues

trisomy 13

47, X_ +13 → 1/16,000 live births; increased risk for congenital heart defects, microcephaly, holoprosencephaly, microphthalmia, polydactyly, clef lip/palate, severe intellectual ability, and cutis aplasia

• most do not survive to term, and of that those do, most don’t survive past 1 year

huntington’s disease

autosomal dominant; HTT gene, age of onset: ~40 years, no treatment or cure; causes motor, cognitive, and psychiatric impairment

coffin-siris syndrome

disrupted subunit in chromatin remodeling complex (SWI/SNF); causes syndromic ID; AD variants in several genes (ARID1A, SMARCA4, etc.)

• microcephaly or macrocephaly

• wide mouth with thick lips

• thick eyebrows andeyelashes

• sparse scalp hair

• hypoplastic nails

• feeding difficulties

• DD and ID

• hearing loss

bloom syndrome

recq helicase disruption; AD variants in BLM gene; fewer than 300 cases known worldwide

• BLM DNA helicase unwinds DNA complexes, repairs DNA double-stranded breaks through homologous recombination, resolves replication forks that have stalled due to DNA damage, and prevents excess sister chromatid exchange

• Cytogenetically, there is a high incidence of chromosome breaks, sister chromatid exchanges (excessive crossing over), and rearrangements

• Increased risk of cancer due to errors in DNA metabolism

• About 1% carrier frequency in AJ population; 75% of cases in non-AJ

• Severe pre- and postnatal growth deficiency with photosensitive skin changes, immune deficiency (recurrent lung, ear, and upper respiratory tract infections), learning disabilities, fertility issues, and early onset cancers, diabetes, and chronic obstructive pulmonary disease

aicardi-goutieres syndrome types 2, 3, and 4

nuclease RNAse H disruption; AR in RNASEH2A/B/C genes cause 50% of cases

• severe, progressive encephalopathy apparent at birth or shortly after

• extreme irritability, slowing head growth (acquired microcephaly), poor feeding, seizures, skin rashes, and significant ID

dyskeratosis congenita

telomere aging syndrome; oral leukoplakia, unusual skin pigmentation, nail dystrophy (all appearing in second decade of life); Ultimately, progressive bone marrow failure due to depletion of stem cells

familial down syndrome

robertsonian translocation between 21 and another acrocentric chromosome; will have 46 chromosomes

cri du chat

deletion of a small terminal portion of the short arm of chromosome 5; deletion size is variable, with different genes associated with aspects of the phenotype

• high pitched cry, microcephaly, high palate, round face, small chin, moderate-severe ID, possible heart defects, clefts

more than 80% are spontaneous (low recurrence risk); 10-15% are derived from parental rearrangement; balanced translocation (high recurrence risk)

smith-magenis syndrome

intercalary deletion (17p11.2); virtually all de novo (rare recurrence unless there’s gonadal mosaicism); findings largely due to mutations in a single gene, RAI1 (haploinsufficiency)

• characteristic facial features: broad square-shaped head, full cheeks, prominent lower jaw; mild-moderate ID, sleep disturbance, self-injurious behaviors

Recurrent deletion (1/15000-25000) → deletion occurs in multiple unrelated individuals

pallister killian syndrome

tetrasomy 12p;

• extreme hypotonia

• high bread forehead

• sparce scalp hair and eyebrows

• hypertelorism

• cupid’s bow lip

• moderate to profound ID and DD

• hearing issues

• congenital diaphragmatic hernia

cat eye syndrome

duplication of 22q;

• coloboma of iris

• down-slanting palpebral fissures

• congenital heart defects

• kidney anomalies

• anal atresia

• normal to mild ID

xeroderma pigmentosum

acute UV sensitivity (cannot pursue nucleotide excision repair); at least 9 different genes associated; AR, variable expressivity

• severe sunburns with blistering

• freckling before age 2

• photophobia and eye surface neoplasms

• greatly increased risk of skin cancers within the first decade of life

• ~25% have neurological symptoms (acquired microcephaly, progressive cognitive impairment, ataxia, SNHL)

lynch syndrome

disrupted mismatch repair enzymes (MLH1, MSH2, MSH6, PMS2); AD hereditary cancer syndrome (dominant inheritance for increased susceptibility; recessive within the cell); predisposes to several types of cancer with highest risk for colon and endometrium

ataxia telangiectasia

two copies of the variant in ATM cancer susceptibility genes → causing predisposition + more significant disease phenotye (AR for disease): primary immunodeficiency; childhood onset cerebellar ataxia, dysarthria, oculomotor apraxia, neuropathy, cognitive impairment, telangiectasias, and cancer predisposition

fanconi anemia

two copies of the variant in cancer susceptibility genes → causing predisposition + more significant disease phenotye (AR for disease): genomic instability due to inability to repair DNA damage; susceptibility to cytotoxic agents, predisposition to hematologic and solid tumors, bone marrow failure