Publications

1. Rayabarapu Pranav Chand, Wankhede Vinit, Varsha Vaidya, Anand SubramaniamIyer, Madhavi Shelke, Shagun Aggarwal, Suvarna Magar, Sumita Danda, Amita Moirangthem, Shubha Rajendra Phadke, Manisha Goyal, Prajnya Ranganath, Mehul Mistri, Parth Shah, Nidhi Shah, Udhaya Hardik Kotecha. Proband only exome sequencing in 403 Indian children with neurodevelopmental disorders: Diagnostic yield, utility and challenges in a resource-limited setting. European Journal of Medical Genetics, Volume 66, Issue 5, 2023.
   Abstract : Whole exome sequencing is recommended as the first tier test for neurodevelopmental disorders (NDDs) with trio being an ideal option for the detection of de novo variants. Cost constraints have led to adoption of sequential testing i.e. proband-only whole exome followed by targeted testing of parents. The reported diagnostic yield for proband exome approach ranges between 31 and 53%. Typically, these study designs have aptly incorporated targeted parental segregation before concluding a genetic diagnosis to be confirmed. The reported estimates however do not accurately reflect the yield of proband only standalone whole -exome, a question commonly posed to the referring clinician in self pay medical systems like India. To assess the utility of standalone proband exome (without follow up targeted parental testing), we retrospectively evaluated 403 cases of neurodevelopmental disorders referred for proband-only whole exome sequencing at Neuberg Centre for Genomic Medicine (NCGM), Ahmedabad during the period of January 2019 and December 2021. A diagnosis was considered confirmed only upon the detection of Pathogenic/Likely Pathogenic variants in concordance with patient’s phenotype as well as established inheritance pattern. Targeted parental/familial segregation analysis was recommended as a follow up test where applicable. The diagnostic yield of the proband-only standalone whole exome was 31.5%. Only 20 families submitted samples for follow up targeted testing, and a genetic diagnosis was confirmed in twelve cases increasing the yield to 34.5%. To understand factors leading to poor uptake of sequential parental testing, we focused on cases where an ultra-rare variant was detected in hitherto described de novo dominant neurodevelopmental disorder. A total of 40 novel variants in genes associated with de novo autosomal dominant disorders could not be reclassified as parental segregation was denied. Semi-structured telephonic interviews were conducted upon informed consent to comprehend reasons for denial. Major factors influencing decision making included lack of definitive cure in the detected disorders; especially when couples not planning further conception and financial constraints to fund further targeted testing. Our study thus depicts the utility and challenges of proband-only exome approach and highlights the need for larger studies to understand factors influencing decision making in sequential testing.
2. Asegaonkar P, Kotecha U, Dongre M, Mistri M, Sharda S. Expanding the spectrum of ADNP-related disorder-Antenatally diagnosed congenital diaphragmatic hernia and a novel de novo mutation in ADNP gene. Am J Med Genet A. 2023 Jan;191(1):275-279. Epub 2022 Nov 2.Abstract: De novo heterozygous ADNP variants have been associated with a complex neurological phenotype characterized primarily by neurodevelopmental delay. Cardiac and renal anomalies have additionally been observed in a few patients. All reported cases to date have been ascertained postnatally. Congenital diaphragmatic hernia (CDH) has been previously observed in one child diagnosed with a de novo ADNP-related neurodevelopmental disorder. We report a fetus who presented with syndromic CDH associated with a de novo heterozygous ADNP variant.
3. Kotecha UH, Mistri M, Rayabarapu P, Shah P, Shah N. The diagnostic utility of exome-based carrier screening in families with a positive family history. Am J Med Genet A. 2022 Apr;188(4):1323-1333
   Abstract:Identification of disease-causing variants in families with a history of a suspected recessive disorder is essential for appropriate counseling and reproductive decision making. The present case series depicts the utility of whole exome-based phenotypes-driven carrier analysis in 14 families with a positive family history. A phenotype-based analysis revealed a putative diagnostic yield of 71.4%. Proband sample, though insufficient, was available in only one family, which allowed the diagnosis to be confirmed. In the remaining nine families, despite the detection of heterozygous pathogenic/likely pathogenic variants, only a putative diagnosis was possible due to incomplete proband phenotyping as well as nonavailability of proband samples. We describe the youngest known patient homozygous for a likely pathogenic variant in PPP1R21. He is currently asymptomatic at 7 days of life and has a simplified gyral pattern on neuroimaging. The case series, though small, captures the challenges in the diagnosis of genetic disorders in low to middle income countries with in-equitable health care access. It reinforces the significance of detailed phenotyping in the proband as well as the importance of DNA storage for a conclusive diagnosis. A recurring post-test counseling challenge was risk ascertainment and reproductive decision making in subsequent pregnancies if the detected pathogenic/likely pathogenic variants are co-inherited, in families with a putative diagnosis. When opted for, prenatal testing in such a scenario would be limited in its ability to comment on the fetal status with respect to the disorder in the proband.
4. Parth S Shah, Nidhi D Shah, Hari Shankar P Ray, Ketan K Vaghasia, Sandip C Shah, Mandava V Rao. Mutation analysis of β-thalassemia in 30 families of India: A report. Journal of Clinical and Diagnostic Research. Vol.12(5): GC01-GC06,2018. Abstract: β-Thalassemia is the most prevalent genetic disorder in India. Its traits and coinheritance vary from mild to severe conditions, resulting in thalassemia minor, intermediate, and major, depending upon many factors.
   Seventy-five referral cases for β-thalassemia were analyzed for various β-thalassemia traits, heterozygosity, and homozygosity conditions. Blood phenotypic parameters using cell counter and capillary electrophoresis were investigated. Analyses of eight common mutations of thalassemia in India were carried out using polymerase chain reaction-amplification refractory mutation system, end point polymerase chain reaction, and DNA sequencing methods.Of these (75) referral cases from East-Western Indian region, 68 were positive for β-thalassemia (90.67%). The majority of case types were of β-thalassemia minor (49, 65.33%), followed by HbE traits (6, 8.0%) and β-thalassemia major, including heterozygous and homozygous (5, 6.66%; 4, 5.33%) types and then HbE homozygous (2, 2.66%), as well as one each of the HbE/β-thalassemia and HbD/β-thalassemia (1, 1.34%) combination. Mutation analysis also revealed that the highest frequency of mutation was c.92+5G>C (41, 60.29%) followed by deletion 619bp (9, 13.23%) and c.79G>A (8, 11.76%) in our study group. Five cases (nos. 24, 27, 33, 58, and 71) exhibited coinheritance between β⁰/β⁺ (2), β⁰/β D (1), and c.124_127delTTCT/β⁺ or β⁰(2) affecting the Rajasthani and Gujarati populations in our study of the Western region of India.

We strongly recommend these Western populations for genetic screening before adopting reproductive technologies and interracial marital relations.