Vol. 011
Familial Inherited Disease and Pre-Test Counseling-Case in Genetic Testing

Familial Inherited Disease and Pre-Test Counseling-Case in Genetic Testing【Case information】
Lucy, a 28-year-old woman, is pregnant. Due to her husband's personal history of DiGeorge
Syndrome (also known as 22q11 deletion syndrome), she consulted with her attending physician
regarding the possibility of prenatal testing to determine if the fetus has inherited this disorder.

【Genetic Counseling】
Even with the same clinical diagnosis, a genetic condition can be caused by very different
underlying genetic changes. Genetic confirmation test reports from affected family members canhelp not only to confirm the diagnosis in the family, but also to verify the specific disease-causing
genetic change running in the family.
In this case, based on Lucy’s husband’s test report, the diagnosis of DiGeorge Syndrome isconfirmed to be related to the common and typical 2.54 Mb chromosomal microdeletion. The fetus
has a 50% risk of inheriting the same deletion and developing the condition.
Detail Information for Prenatal Genetic TestingNoninvasive prenatal testing (NIPT)
Some NIPT tests may detect 22q11 deletion syndrome (also known as DiGeorgeSyndrome) as well as other common microdeletion syndromes. However, NIPT is primarily ascreening test, which means there is still possibilities for false-negative and false-positiveresults. If the NIPT test shows a high risk for fetal genetic abnormalities, diagnostic testing,such as amniocentesis, is still necessary for confirmation.
Chromosomal karyotype analysis
The chromosomal karyotype analysis can detect numerical chromosomal variations, suchas gain or loss of a whole chromosome (for example, Down syndrome), as well as structuralvariations, such as gain or loss of a piece of a chromosome. The resolution of a chromosomal
karyotype analysis is approximately 5-10 Mb. This means microdeletions below 5Mb in size,
such as that of DiGeorge syndrome, cannot be detected.

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GGA Genetic Counseling Newsletter – Vol. 011
Familial Inherited Disease and Pre-Test Counseling -Case in Genetic Testing2Fluorescence In Situ Hybridization (FISH)
The typical 3 Mb chromosomal deletion associated with DiGeorge Syndrome can bedirectly screened for by using FISH technology with disease-specific probes (i.e. TUPLE1 orN25). FISH probes are limited to the analysis of known specific diseases and cannot
simultaneously screen for other untargeted diseases on a large scale.
SNP microarray

SNP microarray allows simultaneous assessment of chromosomal gains and losses of all
23 pairs of chromosomes. This means it can test for the known familial DiGeorge syndrome aswell as other small segmental duplications or deletions on all the chromosomes. A SNP
microarray can also detect most abnormalities identifiable through chromosomal karyotypeanalyses. Moreover, SNP microarray can further identify absence of homozygosity (AOH),
which can be associated with uniparental disomy disease (UPD). UPD disorders are notdetectable through karyotype analysis. Chromosomal karyotype analysis and SNP microarraycomplement each other, and together reduces
Copy number variation
SNP allele difference
fetal risk for chromosomal abnormalities.
Chromosome 22Microarray
Chromosome analysis (Karyotype)The 22q11.2 deletion cannot be identified by routine
analysis of G-banded chromosomes or otherconventional cytogenetic banding techniques.

SNP microarray
The SNP array can detect not only copy number variation
and also identifying absence of homozygosity (AOH).

SNP Array Additional Reading：GGA Genetic Counseling Newsletter Vol.009 Uniparental Disomy
Collection of previous GGA Genetic Counseling Newsletters

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GGA Genetic Counseling Newsletter – Vol. 011
Familial Inherited Disease and Pre-Test Counseling -Case in Genetic Testing3【Case Follow-Up】
Lucy eventually decided to proceed with amniocentesis for chromosomal karyotyping and SNPmicroarray testing. In this way, not only would the fetus be screened for the familial DiGeorge
syndrome, other conditions involving large or small chromosomal structural or numerical aberrant
that can occur in the absence of a positive family history can also be screened for.
The results of both karyotype and SNP microarray analysis revealed normal male chromosomecomplement (46,XY) without detectable pathogenic copy number changes.

What is DiGeorge Syndrome
also known as 22q11.2 Deletion Syndrome (22q11.2DS)/CATCH22 Syndrome







Clinical Characteristics
Highly variable clinical features, even within families, including: congenital heart disease,palatal abnormalities, immune deficiency, characteristic facial features, and learning
difficulties…etc.
Prevalence
Around 1/3800-1/7000, known as the most frequent chromosome microdeletion syndrome.
De novo event in more than 90% of affected individuals. About 10% of individuals inherited
the condition from an affected parent.
Inheritance Mode
Autosomal dominant manner
Genetics
Also known as 22q11.2 Deletion Syndrome, characterized by a heterozygous microdeletionon the long arm of chromosome 22. Approximately 85% of individuals with 22q11.2DS
exhibit a heterozygous 3.0 (2.54)-Mb deletion.
Diagnostic Methodology
Chromosomal microarray (CMA) or targeted deletion analysis.
Treatment & Management
Symptomatic treatment and regular follow-ups. There is currently no cure.
Reference: GeneReview: 22q11.2 Deletion Syndrome [Internet]. Seattle (WA): University of Washington, Seattle; 1993. 1999 Sep 23 [updated 2020 Feb 27].

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GGA Genetic Counseling Newsletter – Vol. 011
Familial Inherited Disease and Pre-Test Counseling -Case in Genetic Testing Different genetic testing and methodology serve distinct purposes. Each test has
its own set of advantages, disadvantages, and applicable testing scopes. Detectionof different pathogenic variations requires the utilization of specific genetic testingtechniques.
 Pre-test counseling is essential to gather information on family history, clarify
risk to the pregnancy and formulate appropriate genetic testing strategy.
Choosing a suitable testing methodology to address specific familial variations
ensures obtaining clinically relevant results. Additionally, this approach helps
prevent unnecessary misdiagnoses, miscarriages, and other associated risks that
may arise from inappropriate testing.
 The genetic diagnosis report of the affected family member is crucial for review
for several reasons: Confirming the diagnosis of familial genetic diseases
 Determining the inheritance mode and fetal risk
 Identifying the appropriate genetic testing strategy and methodology for
accurate detection of family-specific pathogenic variations

Suitabletestingplatform

Familyhistory

Pre-test
Counseling

Clinically appropriate results

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improve our newsletter!

Contact GGA Genetic Counseling Team: gcsupport@gga.asia

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