genetics

Congenital

A condition/ trait present at birth

Allele

One of two or more versions of gene

Gene locus

Specific physical location of a gene on a chromosome

Gene mutation

A permanent change in a gene’s DNA sequence that produces something different

Genotype

Unique DNA sequence of an individual, specifically the pair of alleles for a gene

Phenotype

Observable expression of a genotype; typically corresponds to a pt’s clinical features

Polymorphism

Presence of 2 or more variant forms of a specific DNA sequence in a population (single nucleotide polymorphism)

Penetrance

Degree to which a genotype is expressed as a phenotype in an individual

Gene expression

Process by which a gene is activated to produce RNA & proteins

Single gene disorders

• autosomal dominant

• Autosomal recessive

• Sex-linked

Autosomal dominant disorders

• single mutant allele inherited from an affected parent

• Transmission is independent of sex

• Often have a delayed age of onset

• Each child has a 50% chance of inheriting the mutation from an affected parent

Microfibrils

Essential for tissue architecture especially in tendons & other elastin rich tissues

Marfan syndrome (MFS)

• autosomal dominant inheritance

• Caused by mutations in the fibrillin gene located on chromosome 15

• Results in dysfunctional elastic fibers

General appearance of Marfan syndrome

• tall stature w/ long, slender fingers

• Sunken chest

• High-arched palate w/ crowded teeth

• Joint hypermobility

Autosomal recessive disorders

• one mutant allele from each parent

• Manifests only when both alleles are affected

• BOTH parents are typically carriers & unaffected

• Affects both sexes equally

Points to consider in autosomal recessive disorders

• consanguineous mating increases the chance of both parents being carriers

• Age of onset is early in life

• Symptoms tend to more uniform

• Loss of function mutations that impair or eliminate enzyme function

• Inborn errors of metabolism caused by impaired catabolic pathways & lead to accumulation of dietary substances or cellular constituents

Tay-Sachs Disease

• lysosomal storage disease

• Caused by failure of lysosomes to degrade GM2 ganglioside

• High prevalence in Ashkenazi (Eastern European) Jews

• GM2 ganglioside accumulates in lysosomes of all organs especially brain neurons & retina

• Onset typically between 6 & 10 months of age

• Rapid progression of motor & mental deterioration & generalized seizures

Tay-Sachs Disease Key Points

• severe visual impairment that may lead to blindness

• Retinal ganglion cell involvement visible as a cherry red spot in the macula on ophthalmoscope

• Pallor of surrounding retina w/ prominent blood vessels in the central fovea

• Most affected children die before 4 years old

• No cure; supportive tx

Sex-linked disorders

• almost always associated w/ the X chromosome

• Predominantly recessive

• Female heterozygotes are usually asymptomatic

• All males who inherit defective X-linked gene are typically affected

Red-Green Color Vision Defects

• caused by mutations in OPN1LW or OPN1MW genes

• Leads to absent or abnormal pigment production in L(long-wavelength) or M(medium-wavelength) cones

Multifactorial inheritance disorders

• caused by multiple genes (polygenic)

• Often influenced by environmental factors

• May be expressed during fetal life, at birth, or later in life

• Do not follow Mendelian inheritance patterns

Common characteristics of multifactorial inheritance

• typically involves a single organ/tissue

• Risk of recurrence exists for the same/similar defect in future pregnancies

• Increased risk in 1st & 2nd degree relatives of the affected individual

• Risk increases w/ # of affected family members

Cleft lip & palate

• among the most common birth defects

• Originates around the 35th day of gestation

• Caused by disturbances in gene expression (hereditary/environmental)

• Cleft lip w or w/out cleft palate

• Often associated w/ feeding & speech difficulties in children

MtDNA

• maternal pattern

• Double stranded & circular

• 37 genes

• Mutations typically affect tissues & organs w/ high metabolic demand (oxidative phosphorylation dependent)

Mitochondrial Disorders

• Chronic progressive external ophthalmoplegia

• Deafness

• Kearns-Sayre syndrome

• Lever hereditary optic neuropathy

• Leigh disease

Major cause of chromosomal disorders

• spontaneous abortions

• Congenital malformations

• Intellectual disability

In chromosomal disorders errors can occur,

• at conception (abnormal chromosome number)

• During mitosis (affecting the fertilizes ovum or somatic cells)

Structural Chromosomal Abnormalties

• chromosomal damage can cause breakage & rearrangement

• Deletion, translocation, inversion, isochromosome, ring formation, Robertsonian translocation

Inversion abnormality

Break w/ reversal around the centromere

Isochromosome

Faulty centromere division

Ring formation

Two breaks followed by end to end fusion

Robertsonian translocation

• fusion of long arms of 2 different chromosomes

• Most common chromosomal translocation

Aneuploidy

• change in the # of chromosomes

• Ex. Trisomy 13, trisomy 18, turner syndrome

Monosomy

• only one member of a chromosome pair

• Often leads to spontaneous abortion

• Ex. Turner syndrome

Polysomy

• more than two of a particular chromosome

• Trisomy (2N+1)

Nondisjunction

• failure of chromosomes to separate during oogenesis/spermatogenesis

• Major cause of aneuploidy

Trisomy 21 (Down syndrome)

• most common chromosomal disorder

• Caused by nondisjunction in over 90% of cases

• Characterized by 3 copies of chromosome 21

• Risk increases w/ maternal age

Turner syndrome

• Most commonly 45,X

• failure to develop secondary sex characteristics

• Short stature w/ widely spaced nipples

• Gonadal dysgenesis w/ atrophic “streak” ovaries, primary amenorrhea, infertility

• Cystic hygrometer & webbed neck

• Hypothyroidism

• Congenital heart disease

• Increased risk of gonadoblastoma in females

Klinefelter Syndrome

• chromosomal pattern: 47, XXY

• Nondisjunction → extra X chromosome

• Clinical signs usually appear at puberty

• Associated w/ psychiatric disorders, autism spectrum disorders, social & behavioral challenges

Klinefelter Syndrome clinical features

• testicular atrophy

• Eunuchoid body habits

• High-pitched voice

• Female type hair distribution

• Gynecomastia

Serum testing in prenatal screening

• biochemical markers

  • AFP

  • Beta HCG

  • Estradiol

• Cell-free DNA testing

Reproductive hazard

Anything that interferes w/ a couple’s ability to achieve a successful birth; affects fertility, conception, pregnancy, delivery

Teratogen

Agent that causes malformation of an embryo

3 major categories of reproductive hazards

• physical factors

• Biological factors

• Toxic agents

Fetal alcohol spectrum disorder (FASD)

Umbrella term for physical, mental health, behavioral, & cognitive effects caused by prenatal alcohol exposure

TORCH infections

• toxoplasmosis

• Other (syphilis)

• Rubella

• Cytomegalovirus (CMV)

• Herpes simplex virus (HSV)

A 21-year-old male presents for evaluation of tall stature. Physical examination reveals long, slender fingers, pectus excavatum, joint hypermobility, and a high-arched palate. Ophthalmologic exam shows lens subluxation. A mutation in which of the following genes is most likely responsible for his condition?

FBN1

A 6-year-old boy is brought in for evaluation of difficulty distinguishing red and green colors. There is no family history of color blindness, but the patient's maternal grandfather was also affected. Which of the following best describes the mode of inheritance?

X-linked recessive

A 9-month-old infant of Ashkenazi Jewish descent presents with motor regression, seizures, and poor visual tracking. Fundoscopic exam reveals a cherry-red spot on the macula. What is the most likely diagnosis?

Tay-Sachs Disease