Genetics E1- Chromosomal Disorders

What is polyploidy?

Cells have more than 2 complete sets of chromosomes

What is the loss of a singe chromosome?

Monosomy

What is the gain of 1 homologous chromosome

Trisomy

What is the gain of 2 homologous chromosomes?

Tetrasomy

What is aneuploidy?

Loss or gain of 1 or more chromosomes

What accounts for the spontaneous loss of a very high proportion of all human conceptions?

Chromosome anomalies

What is the usual cause of Down syndrome?

Nondisjunction → gamete receives 2 homologous chromosomes (disomy)

What is nondisjunction?

Failure of separation of 1 of the pairs of homologous chromosomes during anaphase of meiosis I (less common during meiosis II)

What condition?

• involves the acrocentric chromosomes

• 2 long arms, MC 14 & 21, are joined (robertsonian translocation)

• results in 45 chromosomes;

• no significant genetic material lost, phenotype is normal

Trisomy 21

What trisomy is Down syndrome?

Trisomy 21

What is the MC structural chromosome abnormality in humans?

Robertsonian translocation

What are the acrocentric chromosomes?

13, 14, 15, 21, 22

The following clinical features are seen in what condition?

• brachycephaly, epicanthic folds, protruding tongue, small ears, upward sloping palpebral fissures

• single palmar crease, small middle phalanx of 5th finger (clinodactyly), wide gap bt 1st & 2nd toes

• ASD/VSDs, atrioventricular canal, PDA

• anal atresia, duodenal atresia, Hirschsprung disease, short stature, strabismus

Trisomy 21

What trisomy is Edwards syndrome?

Trisomy 18

What trisomy is patau syndrome?

Trisomy 13

With what trisomies do most infants die in first days or weeks life, or result in severe physical & mental disabilities?

Trisomy 13 & 18

What condition is 47, XXY?

Klinefelter syndrome

The following clinical features are associated with what condition?

• “pear shaped mama’s boy”

• long limbs, tall height

• gynecomastia, hypogonadism, azoospermia

Klinefelter syndrome

What is the treatment for Klinefelter syndrome (47,XXY)?

Exogenous testosterone

What condition is 45,X0?

Turner syndrome

The following clinical features are associated with what condition?

• short stature

• webbed neck

• wide spaced nipples

• premature ovarian failure

• CoA

• normal intelligence

Turner syndrome

What is the treatment for Turner Syndrome (45,X0)?

Exogenous estrogen-progestin & cardio referral for serial echos

The following clinical features are associated with what condition?

• Tall height & relatively small head circumference

• Intelligence 15-20 pts lower than siblings

• 1:1000 female births; most diagnoses incidentally / never

XXX / Triple X syndrome

The following clinical features are associated with what condition?

• Tall stature

• IQ mildly impaired; higher rates of ADHD & Autism

• 1:1000 male births

XYY syndrome

The following clinical features are associated with what condition?

• High forehead, large ears, long face, prominent jaw

• Macro-orchidism

• Connective tissue weakness → hyper mobile joints, MVP

• Intellectual disability

• 1:7000 males

Fragile-X syndrome

What is the MC inherited cause of intellectual disability?

Fragile-X syndrome

What do individuals with either deletion of 4p or 5p present with?

Severe intellectual disability

What condition is deletion of 4p?

Wolf-Hirschhorn syndrome

What condition is deletion of 5p?

Cri-du-chat syndrome

What causes wilms tumor/WAGR syndrome?

Deletion of 11p13

The following features are seen in what condition?

• Wilms tumor (rare renal embryonal neoplasm)

• Aniridia (absence of iris)

• GU abnormalities

• Retardation of growth & development

WAGR syndrome

What condition is a maternally derived 15q11.2-q13 deletion?

Angelman syndrome

What condition is a paternally derived 15q11.2-q13 deletion?

Prader-Willi syndrome

What features are seen in angelman syndrome?

Inappropriate laughter, convulsions, ataxia, severe learning difficulties

What features are seen in Prader-Willi syndrome?

Poor feeding in infancy, later develops hyperphagia / obesity, mild-moderate intellectual disability

What condition is a microdeletion of 22q11.2?

DiGeorge Syndrome

What condition?

• microdeletion at 7q11.23

• outgoing in childhood (“cocktail party manner”) but become withdrawn and sensitive as adults

Williams syndrome

What condition?

• microdeletion at 17p11.2

• behavioral characteristics: self harming, persistently disturbed sleep pattern, characteristic “self-hugging”

Smith-Magenis syndrome

What condition is deletion of 9q34?

Kleefstra syndrome

What condition is deletion of 17q21.31?

Koolen-de Vries syndrome

What condition is deletion of 22q13?

Phelan-McDermid syndrome

Why is genetic counseling highly problematic for deletion 1q21.1 syndrome?

Variable penetrance & lack of highly distinctive features

What are indications for chromosome microarray analysis?

Multiple congenital abnormalities, dysmorphic features, unexplained intellectual disability & neurodevelopmental disorders, disorder of sexual development/ ambiguity, infertility, recurrent miscarriages, & unexplained stillbirth