Clinical Genetics - General = Imprinting Disorders (TRANSFERRED)

Question 1

Reference: Genetics residents in-training examination – Fall 2020

You just got a microarray report back for a patient you saw in your clinic several weeks ago. The child is a 10 month old male with global developmental delay and hypotonia. Read the report below and answer the questions.

CYTOGENETICS REPORT

Clinical information: 10m male with global developmental delay, hypotonia

Genomic Microarray Platform: CytoScan HD array (ThermoFisher Scientific)
Genome Build: NCBI Genome Build 37 (UCSC hg19)

RESULT: arr[hg19]15q11.2q13.1(22,770,421-28,547,716)x3

INTERPRETATION: Male with 5.8 Mb pathogenic copy number gain

This copy number gain involves the 15q11.2-q12 Prader-Willi/Angelman syndrome critical region.

a) You test both parents for the variant and it arose de novo. Why does it matter whether the variant arose from the maternal or paternal chromosome?
b) How might you determine the parental origin of the copy number gain in the laboratory?
c) Name 2 genes that may be related to the pathogenicity of copy number variants in this region.

Answer 1

a) The PW/AS syndrome critical region is imprinted.
Maternally derived microduplications at 15q11.2-q13 have been associated with developmental delay, hypotonia, autism and other neuropsychiatric disorders, whereas individuals with paternally derived microduplications of this region are minimally symptomatic. Thus determination of the parent-of-origin may give prognostic information, or, if paternally derived, may lead you to look for other possible causes of hypotonia and developmental delays in this patient.

b) DNA Methylation analysis of the 15q11-13 region. The most common method is methylation-specific multiplex probe ligation assay (MS-MLPA), which will give a methylation ratio of ~0.7 if an extra maternal copy or ~0.3 if extra paternal copy.

c)
Maternally expressed: ATP10A, UBE3A
Paternally expressed: NDN (Nedcin), SNRPN, MAGEL2
Non-imprinted: snoRNAs, GABAA receptor subunits
Note: NIPA1, NIPA2, CYF1P1, and TUGCP5 are only included in Class I CNVs (BP1-BP2), so their contribution is less convincing so would not give marks for these.

Question 2

Reference: Genetics residents in-training examination – Fall 2020

You see a 3-year old child in your clinic with microcephaly, seizures, absent speech, ataxia, and hand flapping. You are considering a diagnosis of Angelman syndrome. What are the four (4) genetic mechanisms that can cause this disease?

Answer 2

Maternal deletion,
Paternal UPD,
UBE3A mutation,
Imprinting centre mutation)