The evolving genetic etiology of conotruncal anomalies.

OBJECTIVE: To assess the diagnostic yield of genetic testing for antenatally detected conotruncal defects. METHOD: This was a retrospective analysis of all antenatally detected cases of conotruncal anomalies over a 4-year period. Patients were offered antenatal and postnatal genetic testing including QF-PCR, microarray and exome sequencing (ES) antenatally or genome sequencing (GS) postnatally on a case-by-case basis. RESULTS: There were 301 cases included. Overall, there were pathogenic genetic findings in 27.6% of the cases tested (53/192). The commonest finding was 22q11.21 deletion (20/192 cases, 10.4%), followed by trisomy 21 (6/192, 3.1%). There were 249 cases of isolated conotruncal anomalies, of which 59.8% (149/249) had genetic testing and 22.8% (34/149) had pathogenic findings. ES/GS was performed in five cases with no pathogenic findings. There were 52 cases of non-isolated contruncal anomalies, of which 82.7% (43/52) had genetic testing. ES/GS was performed in 11 cases in this group and increased the yield of clinically significant diagnoses from 32.6% (14/43) to 44.2% (19/43). CONCLUSION: Genetic abnormalities are present in over one quarter of cases of antenatally detected conotruncal anomalies. The commonest abnormality is 22q11.21 deletion. Exome sequencing or genome sequencing leads to a significant increase in genetic diagnosis in non-isolated cases.

A novel SMOC1 pathogenic homozygous variant in a fetus with mesomelia of the lower limbs, micrognathia and hypertelorism and an incidental finding of CYP21A2-related congenital adrenal hyperplasia.

Trio exome sequencing was performed on a fetus with bilateral mesomelia of the lower limbs with significant angulation of the tibial bones, micrognathia and hypertelorism detected on ultrasound scan at 19 + 0 weeks gestation. The couple is consanguineous. A homozygous pathogenic frameshift variant in the SMOC1 gene (c.339_340del p.(Phe114Cysfs*40)) was detected and both parents were shown to be heterozygous. Pathogenic variants in the SMOC1 gene are associated with microphthalmia with limb anomalies which multidisciplinary team discussion determined to be causal of the scan anomalies detected. The fetus was also a compound heterozygote for CYP21A2 pathogenic variants, confirming a second diagnosis of non-classical congenital adrenal hyperplasia, which was felt incidental to the scan findings. The risk that this couple's next pregnancy would be affected by either of these disorders is 1 in 4 (25%) and demonstrates the importance of genetic diagnoses for the family and implications for future pregnancies.

Prenatal diagnosis of mucopolysaccharidosis type VII facilitating treatment in neonatal period.

Duo exome testing was performed on a fetus conceived via in vitro fertilization with an egg donor. The fetus presented with non-immune hydrops fetalis (NIHF) at 20 + 0 weeks gestation. Two variants were detected in the GUSB gene. Biallelic pathogenic variants cause mucopolysaccharidosis type VII (MPS-VII), which can present with NIHF prenatally. At the time of analysis and initial report, one variant was classified as likely pathogenic and the other as of uncertain clinical significance. Biochemical testing of the amniotic fluid supernatant showed elevated glycosaminoglycans and low ß-glucuronidase activity consistent with the diagnosis of MPS-VII. This evidence allowed the upgrade of the pathogenicity for both variants, confirming the diagnosis of MPS-VII. The infant was born at 36 + 5 weeks and enzyme replacement therapy (ERT) using vestronidase was initiated at 20 days with planning for hematopoietic stem cell transplant ongoing. The ERT therapy has been well tolerated, with decreasing quantitative urine glycosaminoglycans. Long-term follow up is required to determine whether treatment has been successful. This case demonstrates the utility of alternative testing methods to clarify the pathogenicity of variants and the clinical utility of obtaining a diagnosis antenatally in facilitating treatment in the neonatal period, and specifically highlights MPS-VII as a treatable cause of NIHF.