Clinical Utility of Prenatal Exome Sequencing - Achieving a high diagnostic yield with careful patient ascertainment - Congenica
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Clinical Utility of Prenatal Exome Sequencing
Achieving a high diagnostic yield with careful patient
ascertainment
Dr Tessa Homfray
Consultant Medical Genetics
Why do we need new tests in prenatal diagnosis? § Accurate prenatal diagnosis § Prenatal Management § Prenatal Treatment § Management of Labour § Postnatal Treatment § Parental Choices
Tests available at present § DNA tests for known single gene disorders within the family § Chromosome test by Karyotype /aCGH
The problem for diagnostic single gene testing § Time for DNA panel tests + exomes have taken too long § Multiple mutations/genes causing the possible disorder § Prenatal Phenotype lacks a lot of the postnatal information § Prenatal Phenotype maybe different to the postnatal phenotype
Diagnosis by Exome Sequencing
§ How to test?
§ Full Exome
§ Clinical Exome
§ Targeted ExomeSelection of cases § Multiple Congenital Anomalies § Skeletal Dysplasias § Fetal hydrops § Renal Malformations § Micrognathia & Facial Malformations § Cardiac Malformations
Case Selection
§ Important to understand aetiology of a disease
§ Terminal transverse defect
§ Important to (try and) understand disease spectrumImplementation of rapid exome sequencing
for prenatal diagnosis
§ Tested over 60 fetuses
§ Many more suitable limited at present to 1-2/week by cost
§ Singleton, duo, trio or quads
§ Both ongoing pregnancies and postmortem cases
§ Diagnostic yield of ~40%Reporting Strategy
g Dominant Disorder
– De Novo dominant mutations in fetuses with a phenotype that is compatible with mutations within the
gene
– If not de Novo parental phenotype has to be quite specific
g Autosomal Recessive Disorder
– Mutations confirmed in trans by trio exome
– Phenotype compatible with mutations within the gene
g Fetal Phenotyping very important to try and minimise VUSCase 1: Fetus with Micrognathia § 1st pregnancy conceived on 6th attempt of IVF § 12 week scan – micrognathia § 16 weeks reviewed with further scan by fetal medicine doctor + clinical geneticist
Case 1: Fetus with Micrognathia § Mother small chin § Fetus confirmed with isolated micrognathia
Case 1: Fetus with micrognathia § Targeted exome requested on the mother § Very precious pregnancy and did not want an invasive test § No definitive mutation identified § BUT…
Case 1: Fetus with micrognathia Variant of uncertain significance observed in KCNJ2
Case 1: Fetus with micrognathia
KCNJ2
§ Anderson Tawil Syndrome
§ Dysmorphic features – including micrognathia
§ LQT associated with sudden death
§ Periodic Paralysis
§ MICROGNATHIA NOT OF SIGNIFICANCE TO CAUSE NEONATAL PROBLEMSCase 1: Fetus with micrognathia
§ Δ Baby & Mother
§ Mother can be monitored for LQT and treated
§ (avoid sudden death with Rx)
§ Baby not going to have significant micrognathia to cause serious problems in childhood
§ Rx for possible arrhythmias as appropriateCase 2: Fetus with short long bones § Normal 1st trimester scan § 20 week scan long bones on 5th centile and possible fractures § Chest not narrow, marginal abnormal shaped chest § Reviewed jointly with fetal medicine
Case 2: Fetus with short long bones
Gene HGVS Zygosity Disorder
ALPL NM_00478.4: c.920C>T Heterozygous Hypophosphatasia
NP_000469.3: p.(Pro307Leu)
NM_00478.4: c.997+3A>G HeterozygousCase 2: Fetus with short long bones
Hypophosphatasia
§ Different phenotypes
§ Prenatal disease mimics osteogenesis imperfecta (OI)
§ Prenatal disease can look more serious than is the case postnatally
§ The scans do not look like the severe phenotype
§ Treatment available with Asfotase alphaCase 2: Fetus with short long bones Can we be certain? § Father has low Alkaline Phosphatase (ALP) § Maternal ALP inaccurate in pregnancy and not tested
Case 3: Fetus with short long bones § 1st baby non consanguineous couple § Short long bones at 20 week scan § Possible bowing of femur § Referred for 2nd opinion
G139991 Case 3: Fetus with short long bones
G139991 Case 3: Fetus with short long bones
Case 3: Fetus with short long bones
Gene HGVS Zygosity/ Disorder
Inheritance
COL1A NM_000088.3: c.1678G>A Heterozygous Osteogenesis imperfecta, type I, II, III, IV; Caffey
NP_000079.2: p.(Gly560Ser) / De novo disease; Ehlers-Danlos syndrome; arthrochalasia
type 1
This variant has been reported previously in the heterozygous state in individuals with congenital
fractures, poor growth, bone deformities, blue sclera and dentinogenesis in association with OI
types I or IV
(Mackay et al., 1993; Reis et al., 2005; Stephen et al., 2014; Lindahl et al., 2015; Taillandier et al., 2015).Case 4: Fetus with possible abnormal brain
in the 1st trimester
Family History;
15/40 weeks gestation
(1) absent cerebellar vermis
(2) ventriculomegaly / hydrocephalus
(3) post axial polydactyly
?Joubert/Meckel–Gruber syndrome/Dandy walker syndrome/CiliopathyG139563
Case 4: Fetus with possible abnormal brain
in the 1st trimester
Exome sequencing and analysis with Sapientia™ quickly revealed a likely pathogenic
variant in the OFD1 gene on the X chromosome.
Gene HGVS Zygosity/ Disorder
Inheritance
OFD1 NM_003611.2: c.2424dupT Hemizygous/ ?Retinitis pirmentosa 23; Joubert Syndrome;
NP_0036021.1: p.(Glu809Ter) Maternal Orofaciodigital syndrome I; Simpson-Golabi-Behmel
syndrome, type 2
The causal variant was identified in less than 5 minutes.G139563
Read split in maternal sample suggested maternal mosacism
§ No evidence of maternal phenotype
§ Recurrence risk up to 50%
Fetal hemizygous
(read split 0/27)
Maternal ?mosaic
(read split 71/18)Case 4: Orofacial Digital Syndrome Type 1
§ X linked dominant disorder with male lethality
§ Females may have learning difficulties but otherwise clefting, oral frenula, renal cysts
§ Diagnosis allows accurate prenatal diagnosis and PGD in future pregnancy with up to 50%
Recurrence risk
§ 1st trimester US would not identify female affected fetusesBenefit of exome sequencing for prenatal diagnosis § Alters Prenatal Management § Alters Postnatal Treatment § Alters management of future pregnancies § At present our pick up is about 40%
Acknowledgements
South West Thames Regional Genetics
Sahar Mansour
Esther Dempsey
Harris Birthright Centre Suzie Drury
Janna Kenney
Kypros Nicholaides Yogen Patel
John Short
Andrea Haworth
St George’s Fetal Medicine Unit Vijaya Ramachandran
Basky Thilaganathan Laura Reed
Gavin GuyYou can also read
