Challenges and Pragmatic Solutions in Pre-Test and Post-Test Genetic Counseling for Prenatal Exome Sequencing

Figures & data

Table 1 Types of pES Findings, Recommendations for Reporting and Simple Examples Used in Pre-Test Counseling

Finding Category	Subcategory	Definition and/or Subclasses	Recommendations on Reporting pES Findings (Prenatal Panel, Trio Analysis)	Examples that can be used During Counseling
(likely) pathogenic (Class 4/5)	Causative findings	Pathogenic finding explaining the phenotype or matching the indication	YES	CMA: 22q11 microdeletion in a proband with a tetralogy of Fallot pES: CdL in a fetus with a diaphragmatic hernia
	UDs/IFs	Pathogenic findings NOT explaining the phenotype or NOT matching the indication. early-onset treatable diseases early-onset untreatable diseases late-onset treatable diseases late-onset untreatable diseases	Reporting after multidisciplinary discussion: YES YES YES NO	CMA: b) DMD deletion in a male fetuspES: a fetus with a heart defect and a (a) variant in PAH causing phenylketonuria (b) variant in DMD (male fetus) (c) BRCA1 variant (female fetus) (d) NOTCH3 variant causing CADASIL
VUS (Class 3)		VUS are not clinically actionable and generally should not be reported in a prenatal setting	An exceptional cases might be reported after multidisciplinary discussion, e.g., VUS in a known gene matching the fetal phenotype.	E.g., a severe metabolic disorder which can be investigated and treated directly after birth
Status for recessive diseases (class 5 or 4 variant)	Autosomal recessive disorders X-linked disorders	(Likely) pathogenic variants in genes associated with a well characterized recessive disorder If possible deletion/pathogenic variant on the second allele should be excluded	Comprehensive reporting of heterozygous recessive mutations is not recommended. YES, when matching the reason for referral YES, if risk for future pregnancy is ≥25% (e.g., both parents are carriers) X-linked: YES	CMA: DMD deletion in a female fetus pES: (a) pathogenic variant in CFTR gene in a fetus with an echogenic bowel (b) female fetus with a pathogenic variant in DMD
Incidental findings in parental DNA (class 5 or 4 variant)		Abnormalities found by chance, unintentionally, in parents of probands (not in fetus). Very seldom as these will be avoided by using filtering strategies.	Reporting only after multidisciplinary discussion when actionable (e.g., cancer susceptibility, cardiomyopathy) and in concordance to the given informed consent	CMA: Mosaic Turner syndrome discovered during quality control of the array profile

Abbreviations: CADASIL, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy; CMA, chromosomal microarray; CdL, Cornelia de Lange syndrome; pES, prenatal exome sequencing; VUS, variants of unknown significance.

Table 2 Comprehensive List of Items That are Discussed During Pre-Test Counseling for pES

	Issues Discussed During Pre-Test Counseling	Special Attention
1	Discussion on the differential diagnosis for the specific ultrasound anomaly(ies)	Comparison to prenatal cohorts is necessary and counseling solely based on postnatal biased reports is not recommended.
2	Explain the basics of genetics (chromosomes, DNA and when relevant inheritance patterns (e.g., dominant, recessive, X-linked)	If necessary recall the RAD and CMA testing that is already done or in progress.
3	Discuss the potential diagnostic yield of previous tests (RAD, CMA) and further genetic testing
4	Offer pES testing – in our settings currently a broad panel of genes associated with MCA/ID (ca. 3400 genes) and discuss the possible outcomes:	No abnormalities: even open exome sequencing and whole genome CNV analysis may not find a causative variant for the primary indication. This does not mean there is no genetic cause for this primary indication due to technical limitations or incomplete phenotype. Pathogenic variant: causative or unexpected (incidental findings). Discuss the general policy of not reporting VUS.
5	(Written) information is provided. Consent is given by the prospective parent(s).	Remind patients that they may change their consent and in this case they need to contact the counselor.

Abbreviations: CNV, copy number variant; CMA, chromosomal microarray; MCA/ID, multiple congenital anomalies/ intellectual disability; RAD, rapid aneuploidy detection; VUS, variants of unknown significance.