Multi-gene testing in neurological disorders showed an improved diagnostic yield: data from over 1000 Indian patients

Ganapathy, Aparna; Mishra, Avshesh; Soni, Megha Rani; Kumar, Priyanka; Sadagopan, Mukunth; Kanthi, Anil; Patric, Irene Rosetta Pia; George, Sobha; Sridharan, Aparajit; Thyagarajan, T C; Aswathy, S L; Hegde, Vidya; Chinnappa, Swathi M; Nayanala, Swetha; Prakash, Manasa B; Raghavendrachar, Vijayashree Gauribidanur; Parulekar, Minothi; Gowda, Vykuntaraju K; Nampoothiri, Sheela; Menon, Ramshekhar; Pachat, Divya; Udani, Vrajesh; Naik, Neeta; Kamate, Mahesh; Devi, Akella Radha Rama; Kunju, Pam; Nair, Mohandas; Hegde, Anaita Udwadia; Kumar, M Pradeep; Sundaram, Soumya; Tilak, Preetha; Puri, Ratna Dua; Shah, Krati; Sheth, Jayesh; Hasan, Qurratulain; Sheth, Frenny; Agrawal, Pooja; Katragadda, Shanmukh; Veeramachaneni, Vamsi; Chandru, Vijay; Hariharan, Ramesh; Mannan, Ashraf U.

doi:10.1007/s00415-019-09358-1

Cited by 27 publications

(11 citation statements)

References 37 publications

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“…Most of these studies were done in experimentally tractable model organisms with a complex nervous system such as Drosophila , Caenorhabditis elegans or rodents and indicate a crucial role of phosphoinositides in orchestrating major subcellular pathways. Over the same period, advances in next generation DNA sequencing technology and related techniques in human genetic analysis have thrown up a large number of DNA sequence variants and suggested links between these variants and human diseases (Guerreiro et al, 2014; Splinter et al, 2018; Ganapathy et al, 2019); such observations are also true for genes involved in phosphoinositide signaling and their potential function in the context of diseases of the human nervous system. However, there have been two major challenges in this area of science (i) the ability to observe and measure aspects of the cell biology of human brain cells and to test the significance of the observations experimentally (ii) evaluating the functional significance of genetic variants reported in the context of brain disorders in genes related to phosphoinositide signaling.…”

Section: Resultsmentioning

confidence: 99%

Phosphoinositides: Regulators of Nervous System Function in Health and Disease

Raghu

Joseph

Krishnan

et al. 2019

Front. Mol. Neurosci.

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Phosphoinositides, the seven phosphorylated derivatives of phosphatidylinositol have emerged as regulators of key sub-cellular processes such as membrane transport, cytoskeletal function and plasma membrane signaling in eukaryotic cells. All of these processes are also present in the cells that constitute the nervous system of animals and in this setting too, these are likely to tune key aspects of cell biology in relation to the unique structure and function of neurons. Phosphoinositides metabolism and function are mediated by enzymes and proteins that are conserved in evolution, and analysis of knockouts of these in animal models implicate this signaling system in neural function. Most recently, with the advent of human genome analysis, mutations in genes encoding components of the phosphoinositide signaling pathway have been implicated in human diseases although the cell biological basis of disease phenotypes in many cases remains unclear. In this review we evaluate existing evidence for the involvement of phosphoinositide signaling in human nervous system diseases and discuss ways of enhancing our understanding of the role of this pathway in the human nervous system’s function in health and disease.

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Section: Resultsmentioning

confidence: 99%

Phosphoinositides: Regulators of Nervous System Function in Health and Disease

Raghu

Joseph

Krishnan

et al. 2019

Front. Mol. Neurosci.

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“…However, specific data of the localization of the variants are not described. 18 The affected amino acid in our patients is in a highly conserved position (GERP 5.11). 11 There is a similar report to our knowledge in the literature of a female patient with a similar mutation in the United Kingdom with age of onset of six years, site of onset of the legs with muscle pain, generalized hypertrophy and severe proximal weakness.…”

Section: Discussionmentioning

confidence: 76%

“…A very low total frequency (0.00001414) of the mutation in gnomAD v.2.1.1 has been reported, with additional information from African population (0.0001201) and from European Finns (0.00003980). 18 It has not been described before in Latino, Ashkenazi Jews, East Asian, European not Finns, or South-Asian populations. The closest case reported in the literature is in an American male adult diagnosed at 22 years old with a positive familial history, consanguinity and a variant affecting the NM_000083.2 transcript, 17 also the Indian population have been described with an occurrence of 8 over 10,012 unrelated population affected with neurological disorders using TrueSight one panel.…”

Section: Discussionmentioning

confidence: 99%

First Two Case Reports of Becker’s Type Myotonia Congenita in Colombia: Clinical and Genetic Features

Olave-Rodriguez¹,

Bonilla‐Escobar²,

Candelo³

et al. 2021

TACG

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Background Becker’s type myotonia congenita is an autosomal recessive nondystrophic skeletal muscle disorder characterized by muscle stiffness and the inability of muscle relaxation after voluntary contraction. It is caused by mutations in the CLCN1 gene, which encodes for a chloride channel mainly expressed in the striated muscle. Most cases have been reported in the European population, and only mexiletine has demonstrated a randomized placebo-controlled, double-blinded effectiveness. Case Presentation We present two male siblings from Colombia with Latino ancestry, without parental consanguinity, with myotonia during voluntary movements, muscle hypertrophy of lower extremities, transient weakness, and severe muscle fatigue after exercise from three years of age. A genetic panel for dystrophic muscle disorders and a muscle biopsy were both negative. Genetic testing was performed in their second decade of life. Both patients’ exomic sequencing test reported the mutation c.1129C >T (p.Arg377*) affecting exon 10 of the CLCN1 , generating a premature stop codon. This mutation was described as pathogenic and observed in only one other patient in the United Kingdom. Conclusion To our knowledge, these are the first cases of Becker’s type myotonia congenita reported in Colombia. Increasing awareness of healthcare providers for this type of disease in the region could lead to the identification of undiagnosed patients. Limited availability of medical geneticists as well as genetic testing may be the cause of the lack of previous description of cases, in addition to the delay in the diagnosis of the patients. Further epidemiological studies can reveal underdiagnosed myotonias in the country and in the Latin-American region.

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“…In this article, we have provided an overview of the data flow that takes place during rare disease diagnosis. Our rare disease diagnostics test, based on the 5000 gene Illumina TruSight One panel, shows a diagnostic yield of ~ 40% 64 which is on par with other groups using WES. However, considering the rapid rate 65 at which new gene-disease associations are discovered, it is possible that diagnostics laboratories like ours will eventually move from smaller targeted panels to WES to avoid the chance of missing imporant genes.…”

Section: Discussionmentioning

confidence: 91%

Data Analysis in Rare Disease Diagnostics

Veeramachaneni

2020

J Indian Inst Sci

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Data Analysis in Rare Disease Diagnostics 1 IntroductionA draft human genome covering ~ 95% of the human genome was first released in 2000 1 . The sequence, commonly referred to as the human reference genome sequence, is a composite sequence created by sequencing and painstakingly assembling DNA obtained from anonymous volunteers of diverse backgrounds. This ~ 3 billion nucleotide-long genome sequence has undergone several revisions over the years and there are still small regions that have remained intractable. It is not an exaggeration to state that all clinical genomics applications today use the reference sequence as the basis for analysis.In this article, we focus on the topic of rare disease diagnosis through sequencing. There are over 8600 rare disease phenotypes documented in OMIM today 2 . The molecular basis for 6200 of these diseases has been traced to 3900 genes in the reference genome. Most rare diseases are caused by just one or two variants present in the patient genome. However, identifying the exact variants from among the more than 5 million small variants that distinguish any individual from the reference genome is an extremely challenging task 3 .There are four major steps in the rare disease diagnosis process-sequencing, variant detection, variant assessment, and variant prioritization. In this article, we take you through these steps explaining the data analysis that happens at each

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Multi-gene testing in neurological disorders showed an improved diagnostic yield: data from over 1000 Indian patients

Cited by 27 publications

References 37 publications

Phosphoinositides: Regulators of Nervous System Function in Health and Disease

Phosphoinositides: Regulators of Nervous System Function in Health and Disease

First Two Case Reports of Becker’s Type Myotonia Congenita in Colombia: Clinical and Genetic Features

Data Analysis in Rare Disease Diagnostics

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