SNP Array for Prenatal Test and
The Importance of Parental Follow-up SNP Array Tests【Abstract】
In this volume we will share the internal GGA data on SNP Array for Prenatal Test with focuseson comparisons of fetal and parental results, the importance of parental follow-up testing andhow it may change provider-patient genetic counseling discussion as well as risk assessment for
the fetus.
In this current analysis:- Nearly 7,000 results from SNP Array for Prenatal Test were analyzed- The rate of abnormality within this population was 4.9%
- About two-thirds of the abnormal results were genetic changes that cannot be detected byroutine chromosome analysis (karyotype)The importance of parental follow-up SNP array testing can be clearly seen when a fetus isfound to carry a genetic change of unclear clinical significance. Determination of whether a genetic
change in the fetus is inherited or not can help delineate the clinical significance of this change
and help reduce parental anxiety. This helps to provide more information for discussion between
the providers and the patients, and prevent potential irreversible action on the pregnancy due toinsufficient information.
In this current analysis:- Parental follow-up SNP array testing was recommended for 180 fetal results- Over 300 parental follow-up SNP array results were analyzed- In cases with known parental information, about 80% of the fetal genetic changes identified
were familial.
- Of the hereditary cases, about half was inherited from the mother and half from the father.
The spectrum of clinical information provided by knowledge of parental status differs based on
the type and the pathogenicity nature of the genetic change identified in the fetus.
Here we present our internal findings in regards to a few commonly encountered scenarios inwhich parental follow-up SNP array test would be recommended. Counseling notes for eachscenario are also provided.

GGA Genetic Counseling Newsletter – Vol. 006【GGA Experience】
Of the close to 7,000 SNP Array for Prenatal Test results, the proportions of abnormal results
are as follows:

About 3.3% of these prenatal samples showed copy number variations(CNV)-microduplications/microdeletions, or loss of heterozygosity (LOH)-risk for uniparental
disomy (UPD) disorders. These are genetic changes not typically detectable with routine
chromosome analysis. In other words, for these patients, if SNP Array was not prenatally pursued,
it is very likely that the child would not been found to have a severe genetic condition until
concerning symptoms develop monthly or years after birth. This illustrates the importance and thebenefit of prenatal testing with SNP array.
Subsequent comparison with parental follow-up SNP array was recommended for 180 fetal
results to better delineate the clinical significance of the fetal genetic change discovered. This canhelp reduce potential uncertainties regarding the fetus. This piece of knowledge also provides

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GGA Genetic Counseling Newsletter – Vol. 006

medical staff and the family additional information for discussion in regards to pregnancy plans.
With the SNP array platform and GGA internal analytical standard and reporting criteria forprenatal arrays, some commonly encountered scenarios in which parental follow-up testing isrecommended are as follows:
A. Likely benign or Variant of uncertain clinical significance (VOUS) CNV: A chromosomal change in which the clinical significance is currently uncertain
 Available literature support and evidence is limited
 Can potentially be benign in nature
B.

Likely pathogenic CNV: A chromosomal change in which there are scientific literature and database to suggest
association with abnormal clinical presentations.
 The change has also been reported in clinically normal individuals.

C.

Loss of heterozygosity / Increased risk for uniparental disomy:
 A chromosomal change in which allelic genotypes reveals LOH in large chromosomal
segments.
 This can be non-pathogenic or may be related to UPD disorders with risk for clinicalabnormality.

The following are individual discussions of each type of the genetic changes:

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GGA Genetic Counseling Newsletter – Vol. 006

A. Likely Benign and Variant of Uncertain Clinical Significance (VOUS) CNV
In this statistical analysis, about 1.2% of the prenatal samples underwent SNP array test
showed CNV (microdeletions or microduplications) of uncertain clinical significance. There iscurrently no strong scientific evidence to suggest these CNVs are associated with clinicalpathogenicity. These CNVs can be likely benign in nature.
The role of parental follow-up testing: If a healthy parent also carries the same genetic change as the fetus, this would suggest
the CNV may more likely be a benign familial variation and the clinical risk to the fetus islikely lower. This CNV can be considered as a likely benign change.
 If the fetal genetic change is de novo (not inherited from parents; a new change in thefetus), the clinical significance of this CNV is uncertain, the clinical risk to the fetus ishigher, and its impact on the future growth and development of the fetus would bedifficult to predict. This variation can be considered as a VOUS change. Genetic counselingfor VOUS can be challenging given the lack of information available and the degree ofunknowns. The family may need to consider their personal values and acceptance levels
for risk and uncertainties.
In our data, about 71% of these types of CNVs are inherited. Half of the cases was maternallyinherited.
This also means, fetal de novo genetic changes that are of uncertain clinical significance(VOUS) only account for less than 0.5% of all prenatal samples that underwent SNP Array test.

Counseling Notes:
1.

There is currently limited knowledge about this type of chromosomal changes. Available
scientific literature and related information are limited.

2.

It is important to collect blood samples for parental follow-up testing to compare withthe fetal results for further risk assessment:- If the fetal genetic change is inherited from a healthy parent, the CNV may morelikely be a benign familial variation and the risk to the fetus is likely lower. There is a
50% recurrence risk for each of the future pregnancies of that parent.
- If the fetal genetic change is de novo (non-familial), the clinical significance is
uncertain and the risk to the fetus is likely higher in contrast. Fetal health outcome isdifficult to predict. The recurrence risk for the couple’s future pregnancies is muchlower.

3.

Detailed prenatal ultrasound surveys can be considered to assess major structuralanomalies in the fetus.

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GGA Genetic Counseling Newsletter – Vol. 006

B. Likely Pathogenic CNV

A likely pathogenic CNV means that the clinical pathogenicity of the chromosomal change isunclear. There are scientific literature and databases to suggest association with abnormal clinicalpresentations; however, the CNV has also been reported in clinically normal individuals.
Generally speaking, this type of genetic changes also occur in the clinically normal (healthy)
population, but the rate of incidence is higher in patient populations with abnormal clinicalsymptoms. These CNVs usually are associated with less than 100% clinical expression rate(incomplete penetrance), and variable expression in terms of clinical presentation and severity.
This means carriers of this type of CNV do not always manifest clinical symptoms, while thesymptoms in those who do may present in different organ systems and may range from mild tosevere.
In this current analysis, about 1.3% of the samples carried this type ofmicrodeletions/microduplications. Of those, 74% were inherited from a parent. About 60% of thefamilial cases were of maternal inheritance. However, due to the nature of its incomplete
penetrance and variable expressivity, whether the fetus will have abnormal clinical phenotypes is
not definitely correlated with the inheritance pattern.

Counseling Notes:
1.

In general, this type of genetic change:- Also occur in the general (clinically normal) populations, but the incidence rate is higher
in patient populations (individuals with abnormal clinical phenotypes)- Have incomplete penetrance: less than 100% penetrance; This means that CNV carriers
do not always manifest clinical symptoms- Have variable expressivity: clinical expression varies in affected body systems andseverity between individuals, even within the same family.
- Even if the mutation was inherited from a healthy parent, there is no guarantee that thechild will be clinically normal like the parent.

2.

If the CNV is inherited:- There is a 50% recurrence risk for each of the future pregnancies of that parent.
- Parents may consider prenatal SNP array test in future pregnancies, or
pre-implantation genetic testing with in vitro fertilization to assess fetal genetic status.
- If a related family member has concerning clinical symptoms, then the CNV may be thecause of his/her condition. This gives the family member a direction in which to pursue
further investigation into the cause of the symptoms, and may end the diagnosticodyssey.

3.

Related family members may also need to concern his/her potential reproductive risks sincehe/she may also inherited the same CNV.

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GGA Genetic Counseling Newsletter – Vol. 006

C. Loss of Heterozygosity / Uniparental Disomy
Loss of heterozygosity (LOH) is a genetic change that can be detected by SNP-based testing
platforms. LOH neither indicate structural defects in the chromosomes nor any gain/loss ofchromosomes or genes. It only describes that pattern of genotypes observed. The LOH region
indicates that the allelic genotypes of a particular genomic loci of a chromosome pair areidentical (homozygous) –AA or BB genotypes. There is no heterozygous genotype – AB.
There are two mechanisms that can result in LOH:
1) Biparental inheritance: the chromosome pair was inherited as expected-one
chromosome from the father and one from the mother. The fetus inherited identicalgenotypes from both parents at the same locus coincidentally. This generally does notdirectly lead to clinically abnormal disorders, though the risk for recessive disorders
may be increased.
2)

Uniparental inheritance: both chromosomes of a pair was inherited from a single parent
only (meaning the two chromosomes came from either the father or the mother only),
known as uniparental disomy (UPD). Clinically, this may lead to UPD disorders andabnormal symptoms.

When the fetal SNP array result reveal LOH of a large chromosomal segment, it is not possible
to differentiate the above two mechanisms of LOH based solely on the fetal results. An LOH resultin the fetal sample must be compared with the parental SNP array results to determine whether
or not the fetal LOH is associated with UPD disease and clinical abnormality.
In this analysis, about 15 prenatal samples were found to have LOH on UPD disease-related
chromosomes. To determine if these fetuses truly are affected with UPD disorders, we conductedcomparisons with parental follow-up SNP arrays. Fortunately, all of the fetuses were not affected
and the families were reassured.

Counseling Notes:
1. Loss of heterozygosity (LOH) and uniparental disomy (UPD) are not associated with copy
number variations or changes in the total number of genes or chromosome. Therefore, theywould not be detected by chromosome analysis or microarrays without SNP probes.
2. SNP probes can detect UPD disorders that lead to clinical abnormality.
3. LOH findings on SNP array analysis are not always associated with UPD disorders andabnormal outcomes. Follow-up comparisons with parental SNP array results arerecommended to identify the pathogenic types.
4. LOH and UPD are mostly sporadic events with low recurrence risk for future pregnancies fora couple.

Note: SNP array can only detect isodisomy UPD, but not heterodisomy UPD.

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GGA Genetic Counseling Newsletter – Vol. 006

There are still much to learn in the world of genetics. Not all chromosomal changes havesufficient information to determine their clinical implication with currently available medical andscientific knowledge. When encountering genetic changes with undetermined clinical significance,
parental follow-up SNP array comparisons can help further delineate the clinical significance andthe risk to the fetus. In some cases, the results of the parental analyses not only help further assess
the level of risk to the fetus, but also help understand more about individual familial characteristicsand potential reproductive risks for other family members. This information may help lower
parental anxiety and concerns, allow providers and patients to have a more comprehensive
counseling discussion, and potentially prevent irreversible pregnancy action made because of thelack of information.
The accumulation of fetal SNP array data and parental results will also allow us to gain
knowledge and better understand our own population-specific characteristics for the people in
Taiwan. This may serve as a valuable resource for case consultations in the future.

Do you have any questions related to genetic counseling?
What topics would you like the GGA Genetic Counseling
Newsletter to discuss?
Your suggestions are greatly appreciated so we can further
improve our newsletter!
Email dress of the GGA Genetic Counseling Team:
gcsupport@gga.asia

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