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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.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.Of the 102 fetuses sequenced, 45 (44%) achieved definitive diagnosis of a Mendelian 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.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.

We report a 32-week fetus conceived of consanguineous parentage which presented with severe early onset oligohydramnios and history of a similarly affected sibling in previous pregnancy. Ultrasonography and autopsy were inconclusive, prompting exome sequencing on fetal DNA. This resulted in identification of a homozygous novel 3' splice-site variation in intron 17 of the ACE gene (NM_000789.3:c.2642-1G>A), confirming diagnosis of autosomal recessive renal tubular dysgenesis, and facilitating prenatal diagnosis in subsequent pregnancy.

Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal (MIM # 610644) is a clinically distinctive form of SRY-negative 46,XX disorder of sex development. It is a rare autosomal recessive disorder caused due to biallelic loss of function mutations in RSPO1 gene. RSPO1 acts by activating the canonical β-catenin pathway and is one of the most important genes controlling female gonadal differentiation. RSPO1-associated disorders of sex development have been described only in three instances in the past. We report fourth such case with additional findings and perform a comparative review of previous phenotypic descriptions, thereby expanding the clinical phenotype of this syndrome.

Mucopolysaccharidoses (MPS), a subgroup of lysosomal storage disorders, are caused due to deficiency of specific lysosomal enzyme involved in catabolism of glycosaminoglycans. To date more than 200 pathogenic variants in the alpha-l-iduronidase (IDUA) for MPS I and ∼500 pathogenic variants in the iduronate-2-sulphatase (IDS) for MPS II have been reported worldwide. The mutation spectrum of MPS type I and MPS type II disorders in Indian population is not characterized yet. In this study, we carried out clinical, biochemical, molecular and in silico analyses to establish the mutation spectrum of MPS I and MPS II in the Indian population. We conducted molecular analysis for 60 MPS-affected patients [MPS I (n = 30) (Hurler syndrome = 17, Hurler-Scheie syndrome = 13), and MPS II (n = 30) (severe = 18, attenuated = 12)] and identified a total of 44 [MPS I (n = 22) and MPS II (n = 22)] different pathogenic variants comprising missense, nonsense, frameshift, gross deletions and splice site variants. A total of 20 [MPS I (n = 14), and MPS II (n = 6)] novel pathogenic sequence variants were identified in our patient cohort. We found that 32% of pathogenic variants detected in IDUA were recurrent and 25% in MPS II. This is the first study revealing the mutation spectrum of MPS I and MPS II patients in the Indian population.

Objective The objective of this article was to ascertain the opinion of lay persons and medical practitioners in India regarding late termination of pregnancies (LTOP) for fetal abnormalities. Methods One hundred and fifty lay persons and 120 medical practitioners were given separate questionnaires and asked their opinions regarding LTOP for prenatally detected fetal abnormalities of varying severity. The views regarding legalisation of LTOP and the acceptability of feticide by the lay persons were also ascertained. Results More than two-thirds of the lay persons and majority (85.8%) of clinicians felt that LTOP should be allowed for fetal conditions with poor prognosis. At least 70% of lay persons felt that LTOP should be legalised for severe fetal abnormalities. For potentially treatable conditions, continuation of pregnancy in late gestation was the preferred option. For lethal malformations like anencephaly and disorders requiring lifelong treatment like meningomylocele and thalassemia major, majority of clinicians (86.7%, 69.2% and 55.8%, respectively) and lay persons (65%, 51% and 25%, respectively) had the opinion that termination of pregnancy can be offered at any gestational age. Conclusion Both the lay persons as well as the medical fraternity in India feel the need to look into revision of legalisation of LTOP particularly for fetal conditions with poor outcome. Copyright © 2011 John Wiley & Sons, Ltd.

Aim: To find association of angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) T704C, methylenetetrahydrofolate reductase (MTHFR) C677T and factor V Leiden (FVL) G1691A polymorphisms with pre-eclampsia (PE) in North Indian women. Material & Methods: In this prospective case-control study, genotyping of 200 pre-eclamptic women and 200 normotensive pregnant controls was performed for the ACE I/D, AGT T/C,MTHFR C/T and FVL G/A polymorphisms. Statistical analysis was carried out using SPSS and Epi Info to estimate their association with PE. The association of these polymorphisms with nonsevere PE and severe PE was separately assessed. Results: The FVL mutation was found in 4% of women and increased the risk of PE twofold (odds ratio [OR] 2.08, P-value 0.03). The MTHFR mutant allele was found to be protective (OR 0.59, P-value 0.01). Both these polymorphisms showed similar association with nonsevere PE (OR 2.149, P-value 0.038 and OR 0.565, P-value 0.222, respectively) but not with severe PE. The ACE I/D and AGT T/C polymorphisms were not found to be associated with PE overall (OR 1.26, P-value 0.11 and OR 1.15, P-value 0.35, respectively), but ACE I/D polymorphism was found to increase the risk of severe PE (OR 1.53, P-value 0.019). Conclusion: FVL mutation is more common in North Indians than previously believed and it predisposes the women to PE. MTHFR mutant allele is paradoxically protective. ACE polymorphism appears to predispose to severe PE but not nonsevere PE. No significant contribution of AGT polymorphism to PE is found.