Objective: Exome sequencing (ES)-based diagnosis of Mendelian diseases in the fetus is limited by paucity of phenotypic information. This study reports the comprehensive phenotypes of some fetuses with Mendelian disorders. Methods: Next generation technology-based sequencing of all coding regions of the genome (Exome sequencing) or targeted gene sequencing using Sanger or next generation platforms was performed in a cohort of deeply phenotyped, cytogenetically normal fetuses with morphological defects. Prenatal ultrasonographic phenotypes and postmortem details including dysmorphology, histopathology, and radiography were ascertained. Novel candidate genes, novel/unusual findings, and unusual genotypes in cases with confirmed Mendelian disorders are described. Results: Of the 102 fetuses sequenced, 45 (44%) achieved definitive diagnosis of aMendelian disorder with 50 pathogenic/likely pathogenic variants. The majority (87%) were autosomal recessive, 69% families were consanguineous, and 54% variants were novel. Dysmorphic syndromes, skeletal dysplasias, and metabolic disorders were the commonest disease categories, ciliopathies and dystroglycanopathies, commonest molecular categories. We describe the first fetal description of six monogenic diseases, and nine cases with novel histological findings. Nineteen cases had novel/unusual findings. Conclusion:This cohort demonstrates how deep fetal phenotypes of some Mendelian disorders can show novel/unusual findings, which have important implications for prenatal diagnosis of these conditions. Key pointsWhat's already known about this topic � Exome sequencing improves the genetic diagnostic yield in fetuses with abnormal perinatal phenotypes.� Knowledge of perinatal phenotypes of Mendelian disorders is limited and this compromises use of exome sequencing in prenatal period.� Dysmorphology plays an important role in recognition of Mendelian disorders.Neelam Saini and Vijaya Sree Venkatapuram have contributed equally

<b><i>Introduction:</i></b> Vein of Galen malformation (VGM) results from an aneurysmal aberration with an arteriovenous shunting of blood and is the most frequent arteriovenous malformation in infants and fetuses. The congenital malformation develops during weeks 6–11 of fetal development. Infants often die from high-output congestive heart failure. VGM is mostly considered as a sporadic condition with minimal recurrence risk in subsequent pregnancies. Mendelian forms of VGM have rarely been described as infrequent phenotypic presentations of 2 disorders: capillary malformation-arteriovenous malformation syndrome (<i>RASA1</i>, <i>EPHB4</i>) and hereditary hemorrhagic telangiectasia (<i>ENG</i>, <i>ACVRL1</i>, and <i>SMAD4</i>), both showing autosomal dominant inheritance. <b><i>Case Presentation:</i></b> Here, we report on a consanguineous couple with recurrent VGM in 2 pregnancies. Both partners were found to be affected by hereditary hemorrhagic telangiectasia due to a known pathogenic heterozygous c.790G&#x3e;A (p.Asp264Asn) variant in <i>ENG</i>. Fetal DNA was unavailable, however in view of the mild phenotype in the couple, along with the severe prenatal presentation in 2 pregnancies, the fetus was presumed to be homozygous for the <i>ENG</i> variant. A subsequent pregnancy revealed a fetus heterozygous for the variant, which had an uneventful perinatal course. <b><i>Conclusion:</i></b> This report highlights a severe perinatal lethal phenotype due to biallelic variants in a gene hitherto known to cause an autosomal dominant disorder.

Hedgehog acyltransferase gene (HHAT)‐associated Nivelon‐Nivelon‐Mabile syndrome (NNMS) is a rare genetic disorder of multiple system involvement with microcephaly, central nervous system malformations, skeletal dysplasia, and 46,XY sex reversal. Other variable and inconsistent features reported in this disorder are muscle spasms, facial dysmorphism, prenatal onset growth restriction, microphthalmia, and holoprosencephaly. This is the sixth postnatal reported patient with biallelic variants in HHAT gene, who presented with microcephaly, short stature, muscle hypertrophy, muscle spasms, and facial dysmorphism. The most prominent and presenting finding in this patient were muscle hypertrophy and muscle spasms which had a clinical response to phenytoin and acetazolamide treatment. Our report emphasizes the phenotypic variability of NNMS and further reiterates muscle spasms as an important clinical manifestation of this extremely rare condition.