Microdeletion/duplication Syndromes

Question 1

1q21.1 del/dup syndrome

Answer 1

1q21.1 del

Question 2

Williams syndrome

Answer 2

7q11.23 del

Question 3

Prader Willi Syndrome

Answer 3

• loss of expression of PATERNAL genes 15q11-q13, including snoRNA
• due to paternal deletion (75%), or maternal UPD (25%)
• hyperphagia and obesity (but FTT as infant due to hypotonia), hypotonia, hypopigmentation, mild ID, hypogonadism/genital hypoplasia, strabismus, scoliosis
• 1/20,000 births

Question 4

16p11.2 del/dup syndrome

Answer 4

16p11.2 del/dup

Question 5

Smith-Magenis syndrome

Answer 5

• 17p11.2 del affecting RAI1
• ID, craniofacial and skeletal abnormalities (e.g., brachycephaly), midface retrusion, speech and motor delays, sleep disturbance, neurological and behavioral features (self-hugging), neuropathy, hearing loss, and obesity
• 1 in 25,000
• 3-5% recurrence risk due to parental mosaicism
• small indels in RAI1 can cause different/more severe phenotypes due to dominant negative effect

Question 6

dup(17)(p11.2p11.2)

Answer 6

-17p11.2 dup

Question 7

DiGeorge syndrome

Answer 7

• AKA Velocardiofacial syndrome
• 22q11.2 del, including TBX1 gene
• Immune, cardiac, palate, growth, skeletal, GI, ENT, genitourinary, neuro, and neurodevelopment isssues
• E.g., Conotruncal heart defects*, hypernasal speech, GERD, dysphagia, ID, psychiatric illness
• interrupted aortic arch, truncus arteriosis, absent pulmonic valve, pulmonic atresia with VSD, Tetralogy of Fallot, complex transposition
• pathogenesis: Chr 22q11.2 has a lot of low copy repeats, which can cause chromosome misalignment.
• 90% de novo, AD
• 1/20,000

Question 8

Cat eye syndrome

Answer 8

22q11.2 dup

Question 9

Azoospermia

Answer 9

Yq11.2 del

Question 10

Microdel/dup rearrangement size

Answer 10

Most common are 0.6-3.5 Mb

Question 11

Cri du Chat syndrome

Answer 11

• 5p deletion (variable sizes)
• technically not a MICROdeletion (can be detected with FISH/karyotype)
• involves genes such as SEMAF, CTNND2, and hTERT (haploinsufficiency)
• breakpoints important to phenotype & prognosis
• 1 : 15,000-50,000
• high-pitched monochromatic cry, microcephaly, broad nasal bridge, epicanthal folds, micrognathia, abnormal dermatoglyphics, and severe psychomotor and mental retardation
• facies evolve over time
• 85% de novo rate, 15% due to parental balanced translocation

Question 12

Wolf-Hirschhorn (4p-)

Answer 12

• “Greek warrior helmet” facies, growth delay, DD, dry skin, scoliosis, CL/CP
• 1/50,000
• 60% de novo, 40% due to parental balanced translocation

Question 13

Monosomy 1p36

Answer 13

• 20% due to parental balanced translocation

- Severe ID, seizures, behavioral issues, hypotonia, corpus callosum agenesis, protuberant eyes, pointed “witch’s chin”

Question 14

22q11.2 duplication syndrome

Answer 14

• More subtle than 22q del

- Mild learning problems, heart defects, urogenital abnormalities, velopharyngeal insufficiency, Cleft Palate

Question 15

Williams-Buren syndrome

Answer 15

• 7q11.23 deletion; affects ELN gene
• “Elfin-like” facies, gregarious and smiling, stellate iris pattern, supravalvular aortic stenosis, hypermobility, significant ID, behavioral issues like ADHD, growth delay, hypothyroidism
• 1/7,500; can be AD

Question 16

Angelman syndrome

Answer 16

• loss of expression of MATERNAL genes 15q11-q13, including UBE3A
• due to maternal deletion (70%), or maternal mutation (20%); paternal UPD only 2% (unlike PWS)
• phenotype severity depends on genetic cause (deletion most severe, pat UPD least severe)
• less distinctive facies than PWS, uplifted arms, prognathia, wide mouth, hypopigmentation, laughing/smiling, “happy puppet syndrome” strabismus, delayed growth, seizures, DD, ataxia
• 1/12,000 to 20,000 births