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Objective: Genetic diseases are an important cause of neonatal and childhood mortality. For couples with a history of demise of previous children, screening for carrier status can be done by exome sequencing (ES) of the parents. Our aim was to describe the clinical utility of "targeted parental ES" in such couples and to assess the utility of reanalysis of parental ES data. Method: We analyzed previous records, including ES reports, of 52 families with demise of previous offspring with a suspected genetic disorder. We also retrieved and reanalyzed raw data of parental ES in FASTQ format from the testing lab. Results: A potential diagnosis was obtained in 30/52 (57.7%) of couples. We found 38/70 (54.3%) novel variants in this cohort. Shared carrier status for more than one autosomal or X‐linked recessive disorder was identified in 18% of couples. Reanalysis of raw data resulted in a reclassification of variants in 15% of cases. Conclusion: Targeted parental ES can be helpful for families with demise of previous offspring with a suspected genetic disorder. Key points: What's already known about the topic? Many genetic disorders can be rapidly identified by exome sequencing (ES), but this is not always done early in the course of illness due to cost constraints, and many children succumb to the illness before a molecular diagnosis is made.ES of parents in such cases has a reported diagnostic yield of 38%–64%. What does this study add? Parental ES had a diagnostic yield of 57.7%, supporting its usefulness for the evaluation of couples with a history of previous loss of offsprings due to a suspected genetic disorder.Shared carrier status for more than one autosomal or X‐linked recessive disorder was found in 18%, suggesting this should be considered with parental ES.Reanalysis of parental exome data resulted in reclassification of variants in ∼15%. [ABSTRACT FROM AUTHOR]

Background: Antenatally detected occipital encephalocele and polycystic kidneys are a common presentation of ciliopathies like Joubert syndrome and Meckel Gruber syndrome which have considerable genetic and phenotypic overlap. Case reports: We describe 3 cases of antenatally diagnosed occipital encephalocele and enlarged kidneys with fetal autopsy, histopathology & exome sequencing results. A novel nonsense variant in the CEP290 gene was reported in first case (Meckel syndrome). The second case shows the importance of fetal exome where the parents were carriers for 2 ciliopathy genes (TMEM138 & SDCCAG8). Diagnosis in this case was confirmed by fetal exome sequencing (Joubert syndrome). Multiexon deletion in TMEM67 and KIF14 present in trans was identified in the third case (Meckel syndrome), likely resulting in digenic inheritance. Conclusion: We report 2 cases of Meckel syndrome with a novel variant and multiexon deletion, and 1 case of Joubert syndrome which depicts the limitations of preconceptional carrier screening in ciliopathies due to overlapping phenotypes. [ABSTRACT FROM AUTHOR]

Epidermolysis bullosa (EB) is a group of rare genodermatoses that is characterized by skin fragility resulting from minor trauma. There are four major subtypes, namely, EB simplex, junctional EB, dystrophic EB and Kindler EB, depending upon the localization of defective protein and resulting plane of blister formation. The phenotype is heterogeneous in terms of severity and majority of them present at birth or neonatal period. Currently, the treatment is mainly supportive and requires multidisciplinary care. The complex molecular pathology creates difficulty in discovering a unified curative treatment approach. But with arduous efforts, significant progress has been made in the development of treatment strategies in the last decade. The management strategies range from targeting the underlying causative factor to symptom-relieving approaches, and include gene, mRNA, protein, cell and combination therapies. In this review, we enumerate the promising approaches that are currently under various stages of investigation to provide effective treatment for patients with EB. [ABSTRACT FROM AUTHOR]

Inborn errors of ketogenesis are rare disorders that result in acute and fulminant decompensation during lipolytic stress, particularly in infants and children. These include mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS) deficiency and HMG-CoA lyase (HMGCL) deficiency. In this series, we describe the clinical, biochemical, and molecular profiles of four patients along with dietary interventions and their outcomes on a long-term follow-up. Two patients each of HMGCS and HMGCL deficiency were evaluated with clinical history, biochemical investigations, including tandem mass spectrometry (TMS) and urine gas chromatography-mass spectrometry (GCMS). Molecular analysis was performed by whole-exome sequencing, as well as exon array validated by long-range polymerase chain reaction. All individuals were diagnosed with acute metabolic decompensation in the early infancy period except one with HMGCL deficiency who had the first presentation at 5 years of age. Central nervous system manifestations, severe metabolic acidosis, hyperammonemia, hypoglycemia with a normal lactate, and absence of urinary ketones were observed in all the affected individuals. The disorder was life-threatening in three individuals and one succumbed to the illness. TMS was nonspecific and urine GCMS revealed dicarboxylic aciduria in HMGCS deficiency. Both the patients with HMGCL deficiency demonstrated elevated 3 hydroxyisovaleryl carnitine levels in TMS and metabolites of leucine degradation in urine GCMS. We identified five novel variants that included a large deletion involving exon 2 in HMGCL gene. There was no evidence of long-term neurological sequelae in the living individuals. Diet with moderation of fat intake was followed in two individuals with HMGCS deficiency. Low leucine and protein diet with moderation of fat intake was followed in the individual with HMGCL deficiency. All affected individuals are thriving well with no further major metabolic decompensation., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)