Microdeletion, Microduplication, & Imprinting Disorders

Wolf-Hirschhorn syndrome

• Mutation:

  • 4p16.3 deletion

• Gene(s):

  • WHSC1

  • WHSC2 

  • 85% of cases are de novo

• Features:

  • “Greek warrior helmet”

  • microcephaly

  • pre/postnatal growth restriction

  • hypotonia

  • developmental delay

  • seizures

  • skeletal anomalies

  • hearing loss

  • brain anomalies

22q11.2 deletion syndrome

• Mutation:

  • 22q11.2 deletion (3Mb deletion)

• Gene(s): 

  • TBX1

  • 90% of cases are de novo 

• Features: 

  • heart defects: conotruncal (74%), VSD (62%), interrupted aortic arch (52%), ToF (22%)

  • hypoplasia of the thalamus (immunodeficiency)

  • hypocalcemia

  • palate abnormalities

  • developmental delay

  • renal abnormalities

  • increased risk for schizophrenia

• incidence: 1 in 4000

Williams syndrome

• Mutation:

  • 7q11.2 deletion (1.5Mb deletion)

• Gene(s):

  • ELN

  • usually de novo in nature

• Features: 

  • infantile hypercalcemia

  • infantile hypothyroidism

  • Elfin facies

  • supravalvular aortic stenosis (75%)

  • “cocktail” personality

  • hoarse voice

• incidence: 1 in 10,000

Prader-Willi syndrome

(PWS)

• Mutation:

  • paternal deletion of 15q11.2-q13

  • maternal uniparental disomy

  • imprinting disorder

• Gene(s):

  • PWS “critical region”

• Features:

  • neonatal hypotonia

  • neonate feeding difficulties

  • compulsive eating in childhood which leads to obesity

  • mild to moderate intellectual disability

  • small hands & feet

  • hypogonadism

  • hypothalamic dysfunction

• Tip: “no papa” = PWS

Angelman syndrome

(AS)

• Mutation:

  • maternal deletion of 15q11.2-q13

  • paternal uniparental disomy

  • UB3A deletion on maternal chromosome

  • imprinting disorder

• Gene(s):

  • UB3A 

  • AS “critical region”

• Features:

  • severe intellectual disability

  • minimal/no speech

  • seizures

  • hand flapping

  • overtly happy 

Smith-Magenis syndrome

• Mutation:

  • 17p11.2 deletion (3.5Mb)

• Gene(s):

  • RAI1

• Features:

  • sleep disturbances

  • behavioral problems

  • self-destructive injurious behavior

  • nail picking

  • sticking items into orifices

  • seizures

  • intellectual disability

  • developmental delays

  • “lick and flip” behavior (lick fingers and flip pages)

1p36 deletion syndrome

• Mutation: 

  • 1p36 deletion

• Gene(s):

  • many candidate genes

• Features: 

  • intellectual disability

  • little-to-no language

  • slow-closing fontanelles

  • behavioral problems (temper tantrums)

  • hypotonia

  • dysphagia (difficulty swallowing)

  • brain abnormalities → seizures

  • distinct facies (short, wide head → microbrachycephaly)

Cri-du-Chat syndrome

• Mutation:

  • 5p deletion

• Gene(s):

  • multiple gene deletion on the p arm of chromosome 5

• Features: 

  • cat-like cry

  • intellectual disability

  • developmental delay

  • microcephaly

  • low birthweight

  • distinct facies (wide-set eyes, low-set ears, small jaw, round face)

Miller-Dieker syndrome 

• Mutation:

  • 17p deletion

• Gene(s):

  • PAFAH1B1

  • YWHAE

• Features:

  • abnormal brain development (lissencephaly)

  • severe intellectual disability

  • seizures

  • developmental delay

  • hypotonia

  • distinct facies: prominent forehead; sunken-in middle of the face (midface hypoplasia); small, upturned nose; low-set and abnormally shaped ears; small jaw; thick upper lip

  • severely shortened life expectancy (avg age is 2 yrs)

WAGR syndrome

• Mutation:

  • 11p13 deletion

• Gene(s):

  • PAX6

  • WT

• Features:

  • Wilm’s tumor (kidney cancer)

  • Aniridia (no iris)

  • Genitourinary anomalies: undescended testes/cryptorchidism (males) or streak gonads or a bicornate uterus (females)

  • Restricted development

  • mental health conditions like anxiety, ADHD, OCD, ASD, depression

  • chronic constipation (~50% of individuals as reported by a 2021 study)

Jacobsen syndrome 

• Mutation: 

  • 11q deletion

  • AKA: 11q terminal deletion syndrome

• Gene(s):

  • many genes

• Features: 

  • characteristic facies: macrocephaly, trigonocephaly (pointed forehead), small, low-set ears

  • Paris-Trousseau (bleeding disorders)

  • congenital heart defects

  • feeding difficulties

X-linked ichthyosis

• Mutation:

  • Xp22.31

• Gene(s):

  • STS

• Features:

  • ichthyosis (dark, scaly skin) that appears at ~birth-4 months

  • may have intellectual disability in individuals who have larger deletions

  • prenatally: absent or low levels of unconjugated estriol (uE3) 

Beckwith-Wiedemann syndrome

• Mutation:

  • 11p15.5

• Gene(s):

  • CDKN1C

  • H19

  • KCNQ10T1

• Features:

  • organomegaly

  • macroglossia

  • ear anomalies

  • hemi-hypertorphy

  • omphalocele

  • neonatal hypoglycemia

  • increased risk for Wilm’s tumor and/or hepatoblastoma

• Mechanism of Disease:

  • loss of methylation of IC2 on maternal chromosome (most likely)

  • unknown cause

  • paternal uniparental disomy (UPD) of 11p15.5

  • mutation of the maternal CDKN1C allele

  • gain of methylation of IC1 on maternal chromosome

  • cytogenetics: translocation, inversions, duplications (least likely)

22q11.2 duplication syndrome

• Mutation:

  • duplication

• Gene(s):

  • TBX1

• Features:

  • developmental delays

  • intellectual disability

  • slow growth

  • hypotonia

  • many individuals are unaffected (no obvious physical or intellectual disabilities)

7q11.23 duplication syndrome 

• Mutation:

  • 7q11.23 duplication (1.5Mb)

• Gene(s):

  • ELN

• Features:

  • speech and language delay

  • hypotonia

  • mild craniofacial anomalies

  • cognitive delay

  • intellectual disability

  • autism

  • some have normal cognitive abilities

15q11.2-q13 duplication syndrome 

• paternal duplication: 

  • normal to developmental delay

  • obesity

  • less severe

• maternal duplication: 

  • autism

  • hypotonia

  • cognitive deficits

  • seizures

  • facial anomalies

Potocki-Lupski syndrome 

• Mutation:

  • 17p112 duplication

  • 90% have a 3.5Mb duplication

• Gene(s):

  • RA1

• Features:

  • infantile hypotonia

  • poor feeding

  • intellectual disability

  • developmental delay

  • autism

  • heart defects