Genetics – Pathology · FCPS Part 1

GENETIC DISORDERS

Chromosomal abnormalities may involve changes in chromosome number or structure.

Syndrome	Chromosomal defect	Important findings
Down syndrome	Trisomy 21	Intellectual disability, characteristic facial features, congenital heart disease
Edwards syndrome	Trisomy 18	Clenched fists, overlapping fingers, rocker-bottom feet
Patau syndrome	Trisomy 13	Cleft lip/palate, polydactyly, holoprosencephaly and severe congenital abnormalities

Important features include:

Dental relevance: Delayed eruption, hypodontia, malocclusion and increased susceptibility to periodontal disease may occur.

Feature	Turner syndrome	Klinefelter syndrome
Typical karyotype	45,X	47,XXY
Phenotype	Female	Male
Stature	Short	Often tall
Gonadal findings	Ovarian insufficiency/streak gonads	Small testes and hypogonadism
Fertility	Often impaired	Often impaired
Classic clue	Webbed neck, coarctation of aorta	Gynecomastia, infertility

Usually one altered allele is sufficient to produce the disorder.

Often shows vertical transmission through generations.
Both sexes can be affected.
An affected heterozygous parent typically has a 50% chance of transmitting the variant to each child.
Variable penetrance and expressivity may occur.

Disorder	Defect/association	Classic clue
Marfan syndrome	FBN1	Tall stature, lens subluxation, aortic root dilation
Achondroplasia	Activating FGFR3 variant	Disproportionate short stature
Huntington disease	CAG repeat expansion	Chorea and progressive neurodegeneration
Neurofibromatosis type 1	NF1	Café-au-lait spots, neurofibromas
Familial hypercholesterolemia	Often LDLR-related	Elevated LDL and premature atherosclerosis
Adult polycystic kidney disease	Often PKD1/PKD2	Multiple renal cysts

MCQ tip: Huntington disease demonstrates anticipation, particularly with paternal transmission.

Usually both copies of a gene must be affected for disease expression.

May skip generations.
Both sexes are affected equally.
Parents are commonly asymptomatic carriers.
With two carrier parents, each pregnancy has a 25% probability of an affected child.

Disorder	Key feature
Cystic fibrosis	CFTR dysfunction
Sickle cell disease	Abnormal β-globin
Phenylketonuria	Phenylalanine hydroxylase deficiency in classic PKU
Tay–Sachs disease	Hexosaminidase A deficiency
Thalassemia	Reduced or absent globin-chain production
Wilson disease	ATP7B defect
Hemochromatosis (common HFE-related form)	Increased iron absorption
Most glycogen storage diseases	Enzyme deficiencies

Typically affect males more frequently because males have one X chromosome.

Disorder	Defect/association
Hemophilia A	Factor VIII deficiency
Hemophilia B	Factor IX deficiency
Duchenne muscular dystrophy	Dystrophin gene variants
G6PD deficiency	Reduced NADPH production
Red-green color blindness	X-linked opsin gene abnormalities
Fragile X syndrome	X-linked repeat expansion; inheritance is not a classic simple recessive pattern

An affected father does not transmit an X-linked variant directly to his sons.

Remember: No father-to-son transmission in X-linked inheritance.

Multifactorial disorders result from combined genetic and environmental influences.

Examples include:

Dental relevance: Nonsyndromic cleft lip and palate commonly have multifactorial inheritance.