17th World Congress in Fetal Medicine

Genetic abnormalities in prenatally diagnosed central malformations Ting YH The Chinese University of Hong Kong, Hong Kong, Hong Kong

Objective To study the range of genetic abnormalities in prenatally diagnosed central nervous system (CNS) malformations.

Methods Genetic tests including karyotyping, chromosomal microarray (CMA) and whole exome sequencing (WES) were performed and analyzed in all fetuses with prenatally diagnosed CNS malformations between the years 2013 and 2017.

Results There were 74 fetuses with congenital CNS malformation diagnosed prenatally, including 30 neural tube defects (18 exencephaly, 8 and 4 myelomeningocele), 20 cerebral midline defects (including 18 and 2 agenesis of corpus callosum), 10 cerebellar malformations (including 8 Dandy Walker Malformation and 2 cerebellar hypoplasia), 6 malformations of cortical development (including 3 , 2 and 1 ) and 8 miscellaneous malformations (including 3 arachnoid cyst, 2 ischemic infarct, 1 dural sinus arteriovenous malformation, 1 intracranial hemorrhage and 1 tumor). Within the 74 fetuses, 56 (76%) had karyotyping and 16 (29%) had chromosomal abnormality, including 12 13, 2 triploid, 1 trisomy 18 and 1 mosaic trisomy 16. Twenty-one out of 40 (53%) fetuses with normal karyotype had CMA and 5 (24%) pathogenic copy number variant (CNV) were detected, including: 3. 6Mb de novo microdeletion at 7q36. 3 involving SHH (causing non- syndromic holoprosencephaly) in a fetus with isolated holoprosencephaly; 269Kb microdeletion at 2q22. 3 involving ZEB2 gene (causing Mowat Wilson Syndrome) in a fetus with agenesis of corpus callosum and hypospadias; 1. 2Mb de novo microdeletion at 17p13. 3 involving LIS1 gene (causing lissencephaly) in a fetus with isolated lissencephaly; tetrasomy 12p (causing Pallister Killian Syndrome) in a fetus with Dandy Walker Malformation, diaphragmatic eventration, ventricular septal defect and polydactyly; 374Kb maternally-inherited microdeletion at Xq28 involving F8 gene (causing Hemophilia A) in a male fetus with arachnoid cyst with atrioventricular septal defect. Two fetuses with normal karyotype and CMA had WES and both showed pathogenic variants. One fetus with isolated agenesis of corpus callosum had compound heterozygous pathogenic variants in DYNC2H1 gene (causing ) with one variant inherited from each parent. The other female fetus with isolated lissencephaly had heterozygous de novo pathogenic variant in DCX gene (causing X- linked lissencephaly).

Conclusion In this series of prenatally diagnosed CNS malformations, 29% had chromosomal abnormality, majority (71%) being trisomy 13 related to holoprosencephaly. In 21 fetuses with normal karyotype, 5 (24%) pathogenic CNVs were identified on CMA. Four pathogenic CNVs were directly disease-causing, including microdeletions involving SHH gene, ZEB2 gene, LIS1 gene and tetrasomy 12p. The remaining pathogenic CNV was incidental but clinically significant finding, as it was a maternally-inherited microdeletion involving F8 gene in the X which would cause Hemophilia A in this male fetus. The carrier mother would have 50% chance of having an affected son and 50% chance of having a carrier daughter, and preimplantation genetic diagnosis (PGD) would be indicated. The 2 pathogenic variants on WES were also directly disease-causing. In the case of compound heterozygous pathogenic variants in DYNC2H1 gene inherited from both parents, 25% of the future offspring would be affected by ciliopathy and PGD would be indicated. In the case of de novo pathogenic variant in DCX gene, one abnormal copy is sufficient to cause X-linked lissencephaly in this female fetus. In conclusion, CMA would detect 24% pathogenic CNV in those prenatally diagnosed CNS malformations with normal karyotype. For those with normal karyotype and CMA, WES may help to elucidate the genetic basis which would have important bearing on future .