M2C Conditions

Kabuki Syndrome

• multiple genes (KMT2D)

• dominant de novo

• long palpebral fissures

• ID, heart defects, cleft palate, GI issues

• poor growth, endocrine abnormalities, feeding problems, hearing loss

Cornelia De Lange Syndrome (CDLS)

• most often dominant de novo

• multiple genes, most common is NIBPL

• extremely variable phenotype

• heart defects, hearing loss, genital anomalies, self-destructive behavior, feeding difficulties

Kleefstra Syndrome

• variant in EHMT1 or del of 9q34.3 (encompassing gene)

• seizures, behavioral changes after puberty (apathy + catatonia), heart/kidney/genital defects, severe respiratory infections

Fanconi Anemia

• pathway protects against genomic instability

  • loss of pathway leads to ch aberrations with a specific increase in the frequency of radial chromosomes

• need 2 mutations in both copies of the same gene: compound heterozygous in trans

• autosomal recessive

  • biallelic pathogenic variants in genes within pathway

• bone marrow failure, skeletal defects, hypopigmentation, early cancer onset, renal/cardiac/GI/reproductive systems affected

Prader-Willi

• paternal loss of active material

• developmental delay

• failure to thrive + feeding problems folled by insatiable appetite as child/adult

• severe hypotonia

• short stature, obesity

• distinct facial features

Angelman

• maternal loss of active material

• ID

• ataxia

• seizures

• non-verbal

• happy disposition

• microcephaly

Prader-Willi/Angelman mechanism

• region on 15q11q13

• typically due to del of this entire region

• assumed to be de novo in child

• if you have a del, you will have either condition

• ch’s parent of origin determines which disorder

achondroplasia

• problem with cell signaling

• gain-of-function mutation

• FGFR3 receptor remains on, telling cartilage to turn into bone

noonan syndrome

• RASopathy

• structural abnormalities of the heart- pulmonary stenosis + hypertrophic cardiomyopathy common

• developmental delay, cafe au lait spots, short stature, kidney + urinary concerns, hypertelorism, impaired clot formation

androgen insensitivity syndrome

• non-functional version of the AR gene

  • AR gene not functional —> patients who are XY fail to fully develop male characteristics during development and puberty, and display female characteristics instead

• body doesn’t respond to androgens

• classified as complete, partial, or mild

• testes develop partially or fully + testosterone is produced normally

• may present with ambiguous genitalia, abnormal female puberty, absence of periods

Barth syndrome

• bad lipid synthesis

• X-linked, affecting males

• nonfunctional tafazzin enzyme

  • gene TAFAZZIN encodes enzyme tafazzin, that helps synthesize and remodel the fatty acid chains into a specific shape/composition

  • correct cardiolipin isn’t formed

• dilated cardiomyopathy (heart failure and abnl heart rhythms)

• neutropenia (low WBCs)

• muscle weakness, growth delay

• elevation of 3-methylglutaconic acid in urine

Tay-Sachs disease

• poor lipid breakdown

• babies born nl and regress, death around age 2

• lysosomal issue- malfunctioning HexA protein cannot break down sugar in ganglioside —> ganglioside accumulates in lysosome

• leads to cell death/malfunctioning

• recessive

• common in ashkenazi jewish population, but can arise in any pt

• progressive neurodegeneration

I Cell disease

• result of protein targeting error

• cellular debris building up in lysosome

• recessive

• infantile and later-onset: both progressive

• skeletal problems, poor growth, coarse features, cardiac problems, airway restriction

familial hypercholesterolemia

• problem w uptake of LDLs

• dominant put pts can survive being homozygous

• leads to increased cholesterol levels in blood, increased risk for heart attack, cholesterol deposits in skin (xanthomas)

• multiple genes that result in lack of LDLR at cell surface

• treat w diet and statins

Cystic Fibrosis

• impairs chloride channel on cells → poor ion movement in and out of cells

• recessive

• affects cells that produce mucus, sweat, and digestive juices: walls of organs have thick layer of these fluids

• multi system involvement

• deltaF508 pathogenic variant in CFTR : impaired chloride transport leads to abnormal ion concentration —> thick mucus outside of the cells

  • deltaF508 causes protein misfolding

  • NEED MEDICATION TO CORRECT PROTEIN MISFOLDING

Phelan-McDermid syndrome

• point variant or deletion of SHANK3

• intellectual developmental disorder

• autism w regression, poor speech, dysmorphic features, sometimes seizures and birth defects

PIGA

• progressive neurodegenerative disorder

• X-linked: mom likely wouldn’t be affected, so knowing variant is unhelpful

• degeneration starts between 1 month and 1st year of life

Holt-oram syndrome

• TBX5

• CHD

• cardiac arrhythmias/conduction defects

• limb anomalies

• may have other skeletal abnormalities

Osteogenesis Imperfecta

• “brittle bone disease”

• dominant

• commonly due to variants in COLA1A1 or COL1A2 (create collagen

• mild to neonatally lethal

• easy fractures, hearing loss, blu sclera, brittle teeth, short stature

• can be a dominant negative variant

Dyskeratosis Congenita

• problem w machinery that maintains telomere length

• multiple genes, multiple inheritance patterns

• triad of sx: fingernail and toenail abnormalities, lacy pigmentation of the skin, oral leukoplakia

• variable expressivity

• pleiotropy (single gene influences multiple traits)

• increased cancer risk and bone marrow failure

• pulmonary fibrosis and GI problems

Li-Fraumeni Syndrome

• germline mutation in TP53

• autosomal dominant

• high lifetime risk for cancer

• multiple cancer types: adrenocortical carcinoma, breast cancer, CNS tumors, osteosarcomas, soft-tissue sarcomas

Lynch syndrome

• germline pathogenic variants in MMR genes

• autosomal dominant

• predisposition to colon cancer, uterine cancer, and other types

fanconi anemia and ataxia telangiectasia

germline pathogenic variants in homologous recombination repair genes

ataxia telangiectasia

• autosomal recessive

• even single mutation can increase cancer risk

• broad spectrum of phenotypes

  • progressive neuronal degeneration

  • ocular telangiectasias

  • variable immunodeficiency

  • cancer susceptibility

• ATM protein part of homologous recombination DNA repair pathway (mutation → repair can’t happen)

Xeroderma pigmentosum

• sunlight sensitivity

• predisposed to skin cancer

• recessive

  • biallelic pathogenic variants in NER pathway genes

Hereditary Transthyretin Anyloidosis (hATTR)

• variants in TTR gene cause protein to become unstable, misfold, and form amyloid deposits

• accumulates in organs, causes sx

• neuropathy, CHF, hypertrophic cardiomyopathy, arrhythmia

Turner syndrome

• 45, X - 50% cases

• 5,X/46,XX or 45,X/46,XY or 45,X/47, XXX– 20-30%

• Structural abnormalities of the X chromosome – 20-30%

• short stature, skeletal differences, heart problems, learning disabilities, delayed or absent puberty, infertility

• horseshoe kidney, webbed neck, lymphedema

22q11.2 del syndrome + smith-magenis syndrome

caused by CNVs

duchenne (absent/nonfunctional) and becker muscular dystrophies (partially functional)

non woking dystrophin leads to:

DMD

• X linked

• progressive muscle weakness

• dilated cardiomyopathy is typical cause of death (usually by 30)

• carrier females usually develop cardiomyopathy

• de novo 1/3 of the time