Imprinting

Question 1

What are the neonatal features of Prader-Willi syndrome?

Answer 1

Neonatal features:
Congenital hypotonia
Feeding problems/FTT
Narrow bifrontal diameter
Almond-shaped eyes
Down-turned mouth
Small hands/feet

Question 2

What are the childhood/adult features of Prader-Willi syndrome?

Answer 2

Childhood/Adult features:
Hyperphagia, obesity
Developmental delay
Behavior problems
Sleep disorder
Short stature
Hypogonadism

Question 3

What is the phenotype of Angelman syndrome?

Answer 3

Developmental delay/absent speech
Microcephaly, brachycephaly, broad jaw
Frequent laughter, happy demeanor
Seizures with specific EEG pattern
Ataxic (jerky) movements of the limbs and trunk

Question 4

What causes Uniparental Disomy in PWS/AS?

Answer 4

Trisomy rescue

Two paternal chr15 in Angelman
Two maternal chr15 in PWS

Question 5

Deletion of the active paternal chromosome 15q11-13 occurs in what percentage in what disorder?

Answer 5

70% of PWS

Question 6

Maternal uniparental disomy (UPD) of chromosome 15q11-13 occurs in what percentage in what disorder?

Answer 6

~29% of PWS

Question 7

Imprinting mutations occur in what percent of PWS?

Answer 7

Some say 1%/some say 5%

Question 8

Deletion of the active maternal chromosome 15q11-13 occurs in what percentage in what disorder?

Answer 8

68% of Angelman

Question 9

Paternal uniparental disomy (UPD) of chromosome 15q11-13 occurs in what percentage in what disorder?

Answer 9

7% of Angelman

Question 10

UBE3A mutations occur in what percentage of Angelman syndrome?

Answer 10

11% of cases

Question 11

Imprinting mutations occur in what percent of Angelman syndrome?

Answer 11

< 0.3% of cases

Question 12

What is the phenotype of Silver-Russell syndrome?

Answer 12

Prenatal-onset growth retardation, short stature, triangular face, blue sclerae, café au lait spots, limb asymmetry, hypoglycemia

Question 13

What causes Silver-Russell syndrome?

Answer 13

Abnormal imprinting of 11p15.5, chr 7

Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes SRS in 35%-50%

Maternal uniparental disomy (mUPD7) causes SRS in 7%-10% of individuals.

There are a small number of individuals with SRS who have duplications, deletions or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7

Rarely, affected individuals with pathogenic variants in CDKN1C, IGF2, PLAG1, and HMGA2 have been described.

Question 14

In Angelman syndrome which mechanism can be inherited and warrant parental testing?

Answer 14

Imprinting center deletions, 15q deletions and UBE3A gene variants

Only one activeUBE3Aalleleis required for normal brain functioning and it has to be mother’s copy. Inheriting from father will not cause AS. Family history may skip multiple generations for AS symptoms.

Question 15

If your patient with known PWS diagnosis and abnormal methylation has a sibling with PWS features, what is the chance this sibling will also have abnormal methylation?

Answer 15

If sibling clinically has PWS, there is a 50% chance.

Suspect father has an PWS IC deletion in his maternal allele (known to occur in ~5% cases).

Question 16

What testing do you order in Russell-Silver syndrome?

Answer 16

Methylation analysis of 11p15.5 ICR1/ICR2 and maternal UPD7 studies may be ordered simultaneously.

Ifmethylation analysisof 11p15.5 ICR1/ICR2 and maternal UPD7 studies are normal,sequence analysisofIGF2,CDKN1C,PLAG1, andHMGA2may be considered.

Question 17

What percentage of Russell-Silver syndrome have non-diagnostic lab studies?

Answer 17

40%

Question 18

What are the management recommendations in Beckwith Weideman syndrome?

Answer 18

Monitor for hypoglycemia, especially in the neonatal period;
Screen for embryonal tumors by abdominal ultrasound examination every three months until age eight years;
Monitor serum alpha-fetoprotein (AFP) concentration every two to three months in the first four years of life for early detection of hepatoblastoma;
Annual renal ultrasound examination for affected individuals between age eight years and mid-adolescence to identify those with nephrocalcinosis or medullary sponge kidney disease;
Consideration of annual or biannual measurement of urinary calcium/creatinine ratio.