Objective: To ascertain the performance of exome sequencing (ES) technology for determining the etiological basis of abnormal perinatal phenotypes and to study the impact of comprehensive phenotyping on variant prioritization. Methods: A carefully selected cohort of 32/204 fetuses with abnormal perinatal phenotypes following postmortem/postnatal deep phenotyping underwent ES to identify a causative variant for the fetal phenotype. A retrospective comparative analysis of the prenatal versus postmortem/postnatal phenotype-based variant prioritization was performed with aid of Phenolyzer software. A review of selected literature reports was done to examine the completeness of phenotypic information for cases in those reports and how it impacted the performance of fetal ES. Results: In 18/32 (56%) fetuses, a pathogenic/likely pathogenic variant was identified. This included novel genotype-phenotype associations, expanded prenatal phenotypes of known Mendelian disorders and dual Mendelian diagnoses. The retrospective analysis revealed that the putative diagnostic variant could not be identified on basis of prenatal findings alone in 15/22 (68%) cases, indicating the importance of comprehensive postmortem/postnatal phenotype information. Literature review was supportive of these findings but could not be conclusive due to marked heterogeneity of involved studies. Conclusion: Comprehensive phenotyping is essential for improving diagnostic performance and facilitating identification of novel genotype-phenotype associations in perinatal cohorts undergoing ES.

PDE10A encodes a dual cAMP-cGMP phosphodiesterase that is enriched in the medium spiny neurons of the corpus striatum in the brain and plays an important role in basal ganglia circuitry. Three unrelated patients with childhood onset chorea and striatal abnormalities on MRI brain with heterozygous de novo variants in PDE10A have been described previously. Two families with eight affected individuals with biallelic mutations in PDE10A have also been described previously. We report a family with multiple affected individuals with childhood onset chorea, striatal abnormalities, and a novel heterozygous mutation, c.1001T>G(p.F334C) in PDE10A which was identified by exome sequencing.

The prevalence of congenital heart disease in children with Down syndrome in Kerala is the highest reported (63.4 %). Ventricular septal defect is the most common heart disease in the present study. The results highlight the changing attitudes of families towards the surgical correction of congenital heart disease in children with Down syndrome. Prevalence of hypothyroidism in Down syndrome in Kerala is 13.6 %.

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We report a boy with Eiken syndrome caused by a homozygous missense variant in Parathyroid hormone 1 receptor (PTH1R) c.103G > A [p.(Glu35Lys)]. Eiken syndrome is a very rare skeletal dysplasia due to bi-allelic variants in PTH1R. Only one affected family has been known to-date. The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities. The phenotype being described here recapitulates the delayed ossification and modeling abnormalities of Eiken syndrome. In addition, supernumerary epiphyses of the tubular bones of the hands and primary failure of eruption of teeth were observed in our proband. This report characterizes Eiken syndrome and confirms that bi-allelic hypomorphic variants in PTH1R are probably to cause this condition.

We report on a series of 514 consecutive diagnoses of skeletal dysplasia made over an 8‐year period at a tertiary hospital in Kerala, India. The most common diagnostic groups were dysostosis multiplex group (n = 73) followed by FGFR3 (n = 49) and osteogenesis imperfecta and decreased bone density group (n = 41). Molecular confirmation was obtained in 109 cases. Clinical and radiographic evaluation was obtained in close diagnostic collaboration with expert groups abroad through Internet communication for difficult cases. This has allowed for targeted biochemical and molecular studies leading to the correct identification of rare or novel conditions, which has not only helped affected families by allowing for improved genetic counseling and prenatal diagnosis but also resulted in several scientific contributions. We conclude that (1) the spectrum of genetic bone disease in Kerala, India, is similar to that of other parts of the world, but recessive entities may be more frequent because of widespread consanguinity; (2) prenatal detection of skeletal dysplasias remains relatively rare because of limited access to expert prenatal ultrasound facilities; (3) because of the low accessibility to molecular tests, precise clinical‐radiographic phenotyping remains the mainstay of diagnosis and counseling and of gatekeeping to efficient laboratory testing; (4) good phenotyping allows, a significant contribution to the recognition and characterization of novel entities. We suggest that the tight collaboration between a local reference center with dedicated personnel and expert diagnostic networks may be a proficient model to bring current diagnostics to developing countries. © 2014 Wiley Periodicals, Inc.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA binding proteins, which aid in maturation, stabilization, and transport of mRNA. They have a significant role in cellular nucleic acid metabolism. The hnRNPs alter gene expression and are linked to various neurodegenerative disorders and cancers. Previously, six unrelated girls with developmental delay, intellectual disability, and hypotonia were found to have de novo heterozygous pathogenic missense variants in HNRNPH2, located on the X chromosome. A gain-of-function effect was proposed for the variant and it was thought to be lethal in males as no surviving males were identified. We describe a family with two affected siblings, one male and one female, with a known pathogenic variant in HNRNPH2, possibly due to maternal germline mosaicism. K E Y W O R D S developmental delay, heterogeneous nuclear ribonucleoproteins, HNRNPH2, hypotonia, intellectual disability, X-linked dominant

Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM# 611726) is a rare autosomal recessive condition associated with pathogenic variants in KCTD7, which encodes the BR-C,ttk and bab/pox virus and zinc finger domain-containing KCTD7 protein. We report four individuals from three Indian families presenting with an initial period of normal development, progressive myoclonic seizures followed by neuroregression and an abnormal electroencephalogram. We identified two novel missense variants, c.458G>C p.(Arg153Pro) and c.205C>G p.(Leu69Val) and one known disease-causing variant, c.280C>T p.(Arg94Trp) in KCTD7 by exome sequencing. We review the literature of 67 individuals with variants in KCTD7.Our study expands the molecular spectrum of KCTD7-related progressive myoclonic epilepsy.