Genetic Testing after Fetal Diagnosis of CHD - PowerPoint Presentation

Slide1

Genetic Testing after Fetal Diagnosis of CHD

July 2020 Journal Club of the Fetal Heart Society

Slide2

Background

Etiology of CHD thought to be combination of genetics and environment

Higher rates of genetic abnormalities found in fetuses with CHD compared to liveborn patients with CHD, thought to be secondary to

in utero

mortality

Establishing genetic diagnosis can guide counselling and management

Recurrence risk

Further investigation for other anomalies

Decision making regarding interventions

Karyotype and chromosomal microarray currently used

Newer genetic testing options are available

Slide3

Slide4

Methods

1,126 fetuses diagnosed with CHD from January 2013-October 2014 at a tertiary referral center in eastern China

Underwent genetic counselling, offered amniocentesis for karyotype and/or CMA

If both negative, offered targeted next-generation sequencing for 77 genes

Identified based on literature review

Potentially pathogenic mutations associated with isolated or syndromic CHD

Sanger sequencing used to confirm variants, also performed for parents

Only pathogenic variants reported to parents

Slide5

Slide6

Results

Karyotype

Chromosomal microarray

Mean gestational age: 25.2 weeks

12%

Slide7

75%

25%

Slide8

3 week turnaround

Slide9

Mutations

243 variants

5 variants

15.9%

Slide10

Pathogenic and likely pathogenic variants

Cardiofaciocutaneous

syndrome, Holt–

Oram

syndrome, Noonan syndrome, CHARGE syndrome, Ellis–van

Creveld

syndrome, Rubinstein–

Taybi

syndrome 1,

Kleefstra

syndrome,

Alagille

syndrome, Char syndrome,

Okihiro

syndrome,Axenfeld

–Rieger syndrome and Kabuki syndrome

Slide11

All pathogenic and likely pathogenic mutations confirmed by Sanger sequencing and found to be

de novo

mutations

Slide12

Change in decision making?

Pathogenic mutation: 6 fetuses

4 families opted for pregnancy termination prior to genetic results being available

Remaining 2 families chose to continue pregnancy after results

Slide13

Conclusions

16% rate of pathogenic or likely pathogenic variant detection in the setting of negative karyotype and CMA

Total detection rate of 29.4% when combined with karyotype and CMA

Lower rates than some other studies, potentially related to patient selection (type of CHD, familial associations,

etc

)

High rates of VUS: 79%

Could decrease as we learn more

Important for prognosis

Slide14

Slide15

Methods

Cohort study: analysis of extended cohort from PAGE study

Systematic review

Slide16

Prenatal Assessment of Genomes and Exomes (PAGE) cohort

Recruited October 2014-May 2018 at centers in England and Scotland

Prenatal detection of an anomaly after 11 weeks gestation (included increased nuchal translucency



4mm)

Invasive testing performed

Informed consent from both parents (>16 years of age)

Negative karyotype or CMA (97% had CMA)

Whole exome sequencing performed for fetal and parental DNA

Variant interpretation based on targeted virtual gene panel evaluating 1628 genes for developmental disorders

Clinical review panel classified variants: pathogenic, likely pathogenic, uncertain significance, benign, likely benign

Slide17

CODE study

Extended PAGE cohort

Selected patients with cardiac related phenotypes (excluding small muscular VSDs)

Confirmed by fetal cardiologists

Coded type of CHD as:

Shunt lesions

Left sided obstructive lesions

Right sided lesions

Complex lesions

Classified into isolated CHD vs multi-system

Multi-system: included fetal growth restriction, single umbilical artery, nuchal thickening

Slide18

Extended PAGE cohort results

Exome sequencing diagnostic yield

12.7% (25/197)

VUS incidence: 5.1%

Slide19

Systematic review

January 2000-October 2019

MeSH

keywords: variations of “exome sequencing” and “prenatal”

Experts contacted

Inclusion:



3 cases CHD undergoing exome sequencing

Testing based on prenatal findings

CMA or karyotype negative

Slide20

Slide21

Data extraction

Phenotype noted by ultrasound

Exome sequencing approach

Genomic variants

Testing turnaround time

Fetal outcome

Exome sequencing result considered positive if “pathogenic” or “likely pathogenic”

Slide22

Results

636 total cases from 18 studies

54% isolated CHD

46% multi-system

CMA prior to exome sequencing in 98%

21% of original cohort had abnormal karyotype/CMA

Pregnancy outcomes

Livebirth 48%

Termination 46%

For studies where documented, median turnaround time for exome sequencing was 42 days (range 7-82)

Several studies decided not to report results during pregnancy

VUS + incidental finding yield: 26% (95% CI 14-39%)

Slide23

Incremental yield/risk difference of exome sequencing was calculated for each study for all CHD

Subgroup analysis for isolated CHD and multi-system if documented

Risk differences were pooled using a random effects model

Slide24

All CHD

Incremental diagnostic yield of exome sequencing: 21% (95% CI 15-27%)

Septal anomalies or TAPVR yield: 41% (19-63%)

Slide25

Isolated CHD

Incremental diagnostic yield of exome sequencing: 11% (95% CI 7-15%)

Slide26

Multi-system CHD

Incremental diagnostic yield of exome sequencing: 37% (95% CI 18-56%)

For studies with >20 cases: 49% (95% CI 17-80%)

Slide27

Pathogenic variants

Most common genetic syndromes identified

Kabuki syndrome (19/96, 19.8%)

CHARGE (8/96, 8.3%)

Noonan syndrome (6/96, 6%)

For syndromes that typically include extra-cardiac involvement, in 54% only isolated CHD was detected prenatally

Most common associated systems of extra-cardiac abnormality

GU (23/52, 44%)

Nervous system (18/52, 35%)

Face (18/52, 35%)

Most pathogenic variants were

de novo and in autosomal dominant disease genes

Slide28

Conclusions

Limited by high heterogeneity of studies

Incremental diagnostic yield with prenatal whole exome sequencing in CHD

Especially for shunt lesions and patients with extra-cardiac anomalies

There remain significant challenges for clinical use of prenatal exome sequencing

Turnaround time

Interpretation of results

Ethical challenges

Slide29

Summary

Incremental diagnostic yield with newer genetic testing options (16% vs 21%)

Higher for certain groups- those with shunt lesions, extra-cardiac involvement

Identification of syndromes with postnatal phenotypes not always seen prenatally

Differential in difficulty with implementation

Whole exome sequencing requires longer time and higher cost

High rates of variants of unknown significance

Slide30

Article Strengths: Hu et al.

Well done study well explained

Cardiac diagnoses were reviewed

136/1136 elected

amnio

Other thoughts?

Slide31

Article Weaknesses: Hu et al.

High failure rate not explained

High VUS

No longer term follow up for developmental/behavioral phenotyping

Slide32

Strengths: Mone

et al.

Large group, senior investigators, field luminaries

Study cohort had phenotyping based solely on prenatal imaging

Slide33

Weaknesses:

Mone

et al.

Cardiac diagnoses based on coding, larger study was done for any/all anomalies

No longer term follow up for developmental/behavioral phenotyping

Industry support is not insignificant

Need for robust bioinformatic, clinical, and ethical pathways

Included growth restriction and SUA

No cost comparison modeling done

Slide34

Remaining questions

Are the barriers currently prohibitive to routine clinical use (time, cost,

etc

)?

Which patients should be offered/recommended testing if karyotype/CMA negative?

Who will pay for it

Will patients want the testing in the US?

Use of targeted gene panels vs whole exome sequencing?

What results to report and how? Whom?

Ethical issues with full disclosure

What about pathologic results unrelated to the pregnancy (BRCA1,2 mutations? Adult onset neurologic diseases?)

How will these articles inform our clinical practice?