Utility of Whole Exome Sequencing in Desperate Prenatal Patients

Document Type

Conference Proceeding

Publication Date

2024

Publication Title

Genetics in Medicine Open

Abstract

Background: We report on two pregnancies with multiple congenital anomalies and previously unknown etiology through standard genetic testing. Exome sequencing (ES) identified homozygous variants in PIGW classified as variants of uncertain significance. Biallelic variants in PIGW have been associated with autosomal recessive disease due to impaired Glycosylphosphatidylinositol Anchored Proteins (GPI-APs) which are involved in embryogenesis, neurogenesis and immune response. Only a few prenatal reports have been published describing a spectrum of manifestations including increased nuchal translucency, polyhydramnios, cleft lip/palate, congenital heart defects, congenital diaphragmatic hernia, omphalocele, genitourinary abnormalities, posterior fossa malformations, and short limbs. This case report emphasizes the utility of ES in prenatal counseling and aims to broaden the clinical spectrum of rare variants to aid in variant re-classification and more definitive anticipatory guidance for families. Case presentation: A 33 year-old G3P0030 has a history of two prior pregnancies with multiple anomalies. The patient’s first pregnancy was an early miscarriage. The patient’s second pregnancy had a normal first trimester ultrasound and maternal serum (QUAD) screen resulted in low risk for aneuploidy, but an elevated MS-AFP value of 4.76 MoM. Ultrasound at 16w3d noted occipital encephalocele, splayed cerebellum, abnormal profile (including frontal bossing, micrognathia and non-visualized nasal bone), small chest (thoracic circumference 12%ile), echogenic bowel, renal pyelectasis, short long bones and suspected congenital diaphragmatic hernia. Echocardiogram noted truncus arteriosus. Karyotype and microarray were normal (XX) by amniocentesis and acetylcholinesterase was negative. The patient elected termination. Fetal pathology noted grossly shortened fingers, bowel constriction, large aortic root twice the diameter of the pulmonic root, and ventricular septal defect. The patient’s third pregnancy had a cystic hygroma at 13w0d. Anatomy ultrasound noted an increased nuchal fold, Dandy-Walker malformation, short long bones and digits, short ribs, absent nasal bone, small chest (thoracic circumference 20%ile), hydro-ureterocele, tapered calvarium, prominent lateral ventricles, abnormal profile (skin thickening at forehead, small nose, prominent upper lip), membranous ventricular septal defect, increased abdominal circumference (99%ile), possible maxillary cleft and enlarged liver. Fetal MRI noted trigonocephaly and/or craniofacial dysplasia, abnormally diminutive inferior frontal lobes possibly fused and mildly prominent lateral and third ventricles with a small inferior cerebellar vermis. Karyotype and chromosomal microarray were normal (XY). A 48 gene skeletal dysplasia panel was negative. The patient elected termination. Fetopsy additionally identified a bilateral cleft palate, poorly formed penis, and anterior left lower quadrant abdominal wall defect with herniation. Prior to the patient’s fourth pregnancy, remaining DNA from the third pregnancy was sent for trio exome sequencing. Results identified homozygous variants in the PIGW gene (c.106A>G; p.R36G) classified as variants of uncertain significance. Each parent was heterozygous. DNA from the patient’s second pregnancy was subsequently also identified to be homozygous for the same variant. Biallelic variants in PIGW have been associated with seizures, profound developmental delay, dysmorphic features and hyperphosphatasia, but a prenatal phenotype was not well described. The patient was counseled regarding the uncertainty of these variants as evidence was insufficient to prove pathogenicity. The patient pursued her next pregnancy which had a normal first and second trimester ultrasound with no fetal anomalies detected. The patient declined prenatal diagnosis. She had an uncomplicated pregnancy and term delivery. Cord blood was sent for mutation analysis which is currently pending and is expected to result prior to presentation of this abstract. Conclusion: Prenatal counseling for rare genetic disorders remains difficult due to limited genotype-phenotype characterizations. Additional phenotypic reports aim to aid in the re-classification of rare variants and broaden phenotypic spectrums to improve the diagnostic yield of exome sequencing, provide clarification in diagnosis and prognosis, and aid in counseling of genetic disorders with a phenotypic spectrum.

Volume

2

Issue

Suppl 1

Comments

2024 ACMG (American College of Medical Genetics and Genomics) Annual Clinical Genetics Meeting, March 12-16, 2024, Toronto, Canada

DOI

10.1016/j.gimo.2024.101694

Link to Full Text

Share

COinS