Abstract. Sengers syndrome is an autosomal recessive mitochondrial disease comprising a tetrad of congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the AGK gene cause Senger syndrome. We describe two unrelated Asian Indian families with two novel mutations, c.909 G>A (p.Trp303Ter) and c.982G>T (p.E328Ter), in the AGK gene. Similar nonsense mutations have previously been reported with a severe phenotype and early infantile death, while this patient is doing well at 3 years, suggesting a mild phenotype.The second child tested positive for two previously reported mutations, c.841C>T (p.Arg281Ter) and c.424-3C>G. The presence of a splice site mutation typically predicts a milder phenotype with one exception reported to date. The second patient we report died at 9 months of age adding to the one previously reported exception.Both these cases add onto the scant literature of genotype phenotype correlation in Sengers syndrome. We emphasize the importance of diagnosis of this clinically recognizable syndrome to counsel families of recurrence risks and option of prenatal diagnosis.

There are innumerable causes of enlarged kidneys along with dysmorphism in the foetus. Various chromosomal microdeletion syndromes, ciliopathies, Zellweger syndrome, Perlman syndrome and congenital disorders of glycosylation. CDG are a large group of syndromes which cause disruption of one of the several synthetic pathways of glycan synthesis. Here, we describe an unusual and extremely rare presentation cause of enlarged foetal kidneys due to a novel missense variant causing Gillessen-Kaesbach–Nishimura syndrome. The role of deep phenotyping is emphasised as it is a pre-requisite for making a diagnosis and establishing a given mutation as pathogenic. The genetic and clinic aspects of the previously published data are also reviewed.

Hereditary ectodermal dysplasias, a group of disorders affecting skin, hair, nails, and teeth, consist of two main clinical forms – hypohidrotic and hidrotic. Clouston syndrome is a hidrotic ectodermal dysplasia characterized by a triad of generalized hypotrichosis, palmoplantar hyperkeratosis, and nail dystrophy. This paper reports a large Indian family with Clouston syndrome but with the absence of palmoplantar keratoderma, one of the features of the typical triad, thus representing phenotypic heterogeneity, in spite of the presence of a common known mutation in GJB6 gene (p.Gly11Arg).

Intellectual disability (ID) is still unexplained in 60% of cases and prenatal diagnosis is very challenging for this condition. A second gravida presented to us at 6 weeks of gestation for counseling. Her previous child had been diagnosed with ID and autism. Detailed family history showed that her brother also had ID. Screening investigations were normal for the affected child. Exome sequencing report revealed variation of unknown significance (VOUS) on SIN3A gene and UPF3B gene. The variation in X-linked UPF3B gene was reclassified as novel pathogenic variation after segregation studies with parents and affected maternal uncle for both the genes variations. An amniocentesis was done at 18 weeks gestation for the novel mutation in the UPF3B gene and the fetus was found unaffected. The patient delivered a healthy male child who is doing well at two years of age. To conclude, we should not disregard VOUS on exome sequencing. Identification of VOUS requires careful genotype-phenotype correlation and segregation studies to counsel parents regarding the risk of having another affected child.

Objectives The aim of this study was to determine the chromosomal abnormalities and other adverse outcomes like miscarriages, intrauterine deaths, structural defects, and genetic syndromes in fetuses with increased nuchal translucency (NT) more than or equal to 95th centile. This study also compared the outcomes in fetuses with NT between 95th and 99th centile and more than 99th centile. Study Design A prospective cohort of 182 patients with isolated increased NT was evaluated by invasive testing. Fetal chromosomes were examined by fluorescent in situ hybridization and karyotype or chromosomal microarray. Euploid pregnancies were followed-up with level II ultrasound and fetal echocardiography. For pregnancies progressing to delivery, the neonates were followed-up till the age of 3 months. Final outcome was reported as normal or abnormal. Collated data for perinatal outcomes was analyzed and compared between fetuses with NT 95th and 99th centile (group I) and NT more than 99th centile (group II). Results Of the 202 patients recruited, 182 patients consented for invasive testing and chromosomal analysis. Of the 182 patients, group I (NT 95–99th centile) included 92 patients and group II 90 patients. Chromosomal abnormalities were present in 50 (27.4%), 14 (7.6%) in group I, and 36 (19.4%) in group II. Of the 132 euploid pregnancies, adverse outcomes were present in 22 (16%) fetuses, 7 (5.3%) in group I, and 15(11.7%) in group II. A normal outcome was present in 110 (60.4%) pregnancies of the 182 fetuses with NT more than or equal to 95th centile. Normal outcome observed in group I was 77.1% and in group II, it was 43.4%. Conclusion An increased NT is associated with poor perinatal outcomes in 39.6% patients. Chromosomal analysis and follow-up for adverse outcome in fetuses with NT more than or equal to 95th centile is important to enable a take home neonatal rate of 60.4%. No pregnancy with increased NT should be discontinued without detailed fetal evaluation for genetic disorders, structural malformation, and fetal growth.