Decoding the Genetics of Recurrent Molar Pregnancy.

Hydatidiform mole is a condition characterised by abnormal trophoblastic hyperplasia and failure of embryonic tissue development. The risk of recurrence is seen to be associated with biallelic maternal mutations in NLRP7, KHDC3 L and PAD16 genes. Women with such mutations have a major risk of reproductive failure and normal pregnancy is seen in only 1.8%. We report the case of a 31-year-old woman with previous three molar pregnancies who on genetic testing was found to be compound heterozygous for pathogenic variants in the NLRP7 gene (c.2738A>G and c.2078G>C). Accordingly, the woman was counselled regarding assisted reproduction with oocyte donation for a normal pregnancy outcome. At present, the patient has an ongoing 5-month pregnancy through oocyte donation.

Next-Generation Sequencing in Unexplained Intellectual Disability.

OBJECTIVES: To determine the diagnostic yield of next generation sequencing (NGS) in patients with moderate/severe/profound intellectual disability (ID) unexplained by conventional tests and to assess the impact of definitive diagnosis on the clinical management and genetic counselling of these families. METHODS: This was a ambi-directional study conducted at Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi. The study comprised 227 patients (prospective cohort - 126, retrospective cohort - 101) in whom NGS based tests were performed. RESULTS: The mean age of study cohort was 4.5 ± 4.4 y (2.5 mo to 37.3 y). The male: female ratio was 1.6:1. The overall diagnostic yield of NGS was 53.3% (121/227) with causative variants identified in 84 known ID genes. Autosomal recessive intellectual disability (ARID) (23.3%, 53/227) was the most common followed by autosomal dominant intellectual disability (ADID) (20.7%, 47/227) and X-linked intellectual disability (XLID) (9.2%, 21/227). The diagnostic yield was notably higher for ID plus associated condition group (55.6% vs. 20%) (p = 0.0075, Fisher's exact test) compared to isolated ID group. The impact of diagnosis on active or long-term management was observed in 17/121 (14%) and on reproductive outcomes in 26/121 (21.4%) families. CONCLUSIONS: There is paucity of data on molecular genetic spectrum of ID from India. The current study identifies extensive genetic heterogeneity and the impact of NGS in patients with ID unexplained by standard genetic tests. The study identified ARID as the most common cause of ID with additional implications for reproductive outcomes. It reiterates the importance of phenotype in genetic testing.

Antenatal Phenotype of Desbuquois Dysplasia.

Desbuquois dysplasia (DBQD) is an uncommon, autosomal recessive disorder with multiple joint dislocations. It is caused by pathogenic variants in CANT1 (calcium-activated nucleotidase 1) [NM_001159773.2]. This study adds to the scant data of nine reported antenatal phenotypes of DBQD. The present paper describes two unrelated consanguineous families with antenatal features of lethal skeletal dysplasia. The defining radiological changes were identified in only one patient who presented in the late second and third trimesters. Solo exome sequencing was performed and two previously reported homozygous variants c.896C>T (p.Pro299Leu) in patient 1 and c.902_906dup (p.Ser303fs*20) in patient 2 were identified. This study highlights the fetal presentations in DBQD and adds to its phenotypic spectrum. A complete clinical workup, including fetal autopsy and radiographs is essential to confirm the diagnosis of lethal skeletal dysplasia. Molecular diagnosis remains the diagnostic modality to define the causative variant. A definitive diagnosis is essential to inform management and offer reproductive care.

Prenatal phenotypic spectrum of full trisomy 18 in an Indian cohort.

Trisomy 18 or Edward syndrome is a chromosomal disorder due to the presence of an extra chromosome 18. We describe the phenotype of five fetuses at different gestational ages, each highlighting a different aspect of trisomy 18. The clinical spectrum included increased nuchal translucency, fetal hydrops, congenital malformations of the central nervous system, congenital heart disease, radial ray defects, and characteristic facial gestalt. We made a comparison of prenatal ultrasonography and the autopsy findings. The fetal autopsy defined the craniofacial and digit anomalies better compared with sonography. The facial features of tall forehead, hypoplastic nares, microstomia, micrognathia, low set abnormal ears along with clenched hands, and short hallux are typical for trisomy 18 and help in planning the targeted cytogenetic or molecular tests. The diagnosis was established by either fluorescence in situ hybridization or quantitative fluorescent polymerase chain reaction or chromosomal microarray in the patients. This communication emphasizes the importance of detailed assessment for craniofacial and limb anomalies on prenatal ultrasonography which can prompt an early evaluation for trisomy 18.

Case Series of Creatine Deficiency Syndrome due to Guanidinoacetate Methyltransferase Deficiency.

Guanidinoacetate methyltransferase (GAMT) deficiency is the second most common defect in the creatine metabolism pathway resulting in cerebral creatine deficiency syndrome (CCDS). We report three patients from two unrelated families, diagnosed with GAMT deficiency on next-generation sequencing. All the probands had happy predisposition as a predominant manifestation in addition to the reported features of global developmental delay, seizures, and microcephaly. This further expands the phenotype of CCDS. The workup for creatine deficiency disorder should be included in the diagnostic algorithm for children with nonsyndromic intellectual disability, especially in those with a happy demeanor. These cases exemplify the utility of magnetic resonance spectroscopy of the brain in the workup of nonsyndromic intellectual disability to diagnose a potentially treatable disorder. In addition, documentation of low serum creatinine may be supportive. Early diagnosis and treatment is essential for better prognosis.

Consensus Statement of the Indian Academy of Pediatrics on Diagnosis and Management of Fragile X Syndrome in India.

JUSTIFICATION: Fragile X Syndrome (FXS) is the most common genetic cause of inherited intellectual disability and autism spectrum disorder (ASD). Early identification results in appropriate management and improvement in functioning. Risk assessment in other family members can lead to prevention of the disorder. This necessitated the formulation of IAP recommendations for the diagnosis and management of FXS in Indian children and adolescents. PROCESS: The meeting on formulation of national consensus guidelines on Fragile X syndrome was organized by the Indian Academy of Pediatrics in New Delhi on 25th February, 2017. The invited experts included Pediatricians, Developmental Pediatricians, Psychiatrists, Pediatric Neurologists, Gynecologists, Geneticists, Clinical Psychologists and Remedial Educators, and representatives of Parent Organizations. Guidelines were framed after extensive discussions. A writing committee was formed that drafted the manuscript, which was circulated among members for critical appraisal, and finalized. RECOMMENDATIONS: The committee recommended that early diagnosis of FXS is crucial for early, timely and appropriate management. The interventions including timely occupational therapy, speech therapy and behavioral modifications help to improve the developmental potential and reduce the maladaptive behavior. Pharmacotherapy may be needed to control and improve behavioral symptoms. In addition, the emergence of targeted treatments such as low dose sertraline, metformin and /or minocycline may also be helpful for behavior, and perhaps cognition. Genetic counselling is helpful to communicate the risk for future children with FXS or permutation involvement.

Mutation-Proved Clouston Syndrome in a Large Indian Family with a Variant Phenotype.

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).