scholarly journals Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Hosneara Akter ◽  
Mohammad Shahnoor Hossain ◽  
Nushrat Jahan Dity ◽  
Md. Atikur Rahaman ◽  
K. M. Furkan Uddin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diseases ◽  
Leigh Syndrome ◽  
Genetic Profile ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Rare Genetic Diseases ◽  
Compound Heterozygous Variants

AbstractCollectively, rare genetic diseases affect a significant number of individuals worldwide. In this study, we have conducted whole-exome sequencing (WES) and identified underlying pathogenic or likely pathogenic variants in five children with rare genetic diseases. We present evidence for disease-causing autosomal recessive variants in a range of disease-associated genes such as DHH-associated 46,XY gonadal dysgenesis (GD) or 46,XY sex reversal 7, GNPTAB-associated mucolipidosis II alpha/beta (ML II), BBS1-associated Bardet–Biedl Syndrome (BBS), SURF1-associated Leigh Syndrome (LS) and AP4B1-associated spastic paraplegia-47 (SPG47) in unrelated affected members from Bangladesh. Our analysis pipeline detected three homozygous mutations, including a novel c. 863 G > C (p.Pro288Arg) variant in DHH, and two compound heterozygous variants, including two novel variants: c.2972dupT (p.Met991Ilefs*) in GNPTAB and c.229 G > C (p.Gly77Arg) in SURF1. All mutations were validated by Sanger sequencing. Collectively, this study adds to the genetic heterogeneity of rare genetic diseases and is the first report elucidating the genetic profile of (consanguineous and nonconsanguineous) rare genetic diseases in the Bangladesh population.

scholarly journals Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

2021 ◽  
Vol 7 (2) ◽  
pp. e558
Author(s):  
Daphne J. Smits ◽  
Rachel Schot ◽  
Martina Wilke ◽  
Marjon van Slegtenhorst ◽  
Marie Claire Y. de Wit ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Splice Variants ◽  
Brain Mri ◽  
Cerebellar Vermis ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Whole Exome

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

scholarly journals Case Report: Whole Exome Sequencing Identifies Compound Heterozygous Variants in TSFM Gene Causing Juvenile Hypertrophic Cardiomyopathy

2022 ◽  
Vol 8 ◽  
Author(s):  
Jamie O. Yang ◽  
Hapet Shaybekyan ◽  
Yan Zhao ◽  
Xuedong Kang ◽  
Gregory A. Fishbein ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Elongation Factor ◽  
Nuclear Gene ◽  
Compound Heterozygous ◽  
Mitochondrial Translation ◽  
Translation Elongation ◽  
Whole Exome ◽  
Compound Heterozygous Variants

We report a case of hypertrophic cardiomyopathy and lactic acidosis in a 3-year-old female. Cardiac and skeletal muscles biopsies exhibited mitochondrial hyperplasia with decreased complex IV activity. Whole exome sequencing identified compound heterozygous variants, p.Arg333Trp and p.Val119Leu, in TSFM, a nuclear gene that encodes a mitochondrial translation elongation factor, resulting in impaired oxidative phosphorylation and juvenile hypertrophic cardiomyopathy.

scholarly journals A Japanese girl with mild xeroderma pigmentosum group D neurological disease diagnosed using whole-exome sequencing

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Takayuki Yokoi ◽  
Yumi Enomoto ◽  
Tomoko Uehara ◽  
Kenjiro Kosaki ◽  
Kenji Kurosawa
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Neurological Disease ◽  
Xeroderma Pigmentosum ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Skin Symptoms ◽  
Group D ◽  
Xeroderma Pigmentosum Group D

AbstractWe report a Japanese girl with mild xeroderma pigmentosum group D neurological disease. She had short stature, cataracts, intellectual disability, and mild skin symptoms. However, she was not clinically diagnosed. Using whole-exome sequencing, we identified compound heterozygous pathogenic variants in ERCC2. In the future, the patient may develop skin cancer and her neurological symptoms may progress. Early genetic testing is necessary to clarify the cause of symptoms in undiagnosed patients.

scholarly journals Whole-Exome Sequencing Identified a Novel Compound Heterozygous Genotype in ASL in a Chinese Han Patient with Argininosuccinate Lyase Deficiency

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Mei Zhao ◽  
Lingling Hou ◽  
Huajing Teng ◽  
Jinchen Li ◽  
Jiesi Wang ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Compound Heterozygous ◽  
Significant Activity ◽  
Argininosuccinate Lyase ◽  
Chinese Han ◽  
Lyase Deficiency ◽  
Pathogenic Variants ◽  
Whole Exome

Pathogenic variants in the argininosuccinate lyase (ASL) gene have been shown to cause argininosuccinate lyase deficiency (ASLD); therefore, sequencing analysis offers advantages for prenatal testing and counseling in families afflicted with this condition. Here, we performed a genetic analysis of an ASLD patient and his family with an aim to offer available information for clinical diagnosis. The research subjects were a 23-month-old patient with a high plasma level of citrulline and his unaffected parents. Whole-exome sequencing identified potential related ASL gene mutations in this trio. Enzymatic activity was detected spectrophotometrically by a coupled assay using arginase and measuring urea production. We identified a novel nonsynonymous mutation (c.206A>G, p.Lys69Arg) and a stop mutation (c.637C>T, p.Arg213∗) in ASL in a Chinese Han patient with ASLD. The enzymatic activity of a p.Lys69Arg ASL construct in human embryonic kidney 293T cells was significantly reduced compared to that of the wild-type construct, and no significant activity was observed for the p.Arg213∗ construct. Compound heterozygous p.Lys69Arg and p.Arg213∗ mutations that resulted in reduced ASL enzyme activity were found in a patient with ASLD. This finding expands the clinical spectrum of ASL pathogenic variants.

Whole-exome sequencing identified compound heterozygous variants in the TTN gene causing Salih myopathy with dilated cardiomyopathy in an Iranian family

2021 ◽  
pp. 1-6
Author(s):  
Mohammad Mahdavi ◽  
Neda Mohsen-Pour ◽  
Majid Maleki ◽  
Mahshid Hesami ◽  
Niloofar Naderi ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnostic ◽  
Metabolic Parameter ◽  
Compound Heterozygous ◽  
Formidable Challenge ◽  
Whole Exome ◽  
Iranian Family ◽  
Compound Heterozygous Variants

Abstract Background: Salih myopathy, characterised by both congenital myopathy and fatal dilated cardiomyopathy, is an inherited muscle disorder that affects skeletal and cardiac muscles. TTN has been identified as the main cause of this myopathy, the enormous size of this gene poses a formidable challenge to molecular genetic diagnostics. Method: In the present study, whole-exome sequencing, cardiac MRI, and metabolic parameter assessment were performed to investigate the genetic causes of Salih myopathy in a consanguineous Iranian family who presented with titinopathy involving both skeletal and heart muscles in an autosomal recessive inheritance pattern. Results: Two missense variants of TTN gene (NM_001267550.2), namely c.61280A>C (p. Gln20427Pro) and c.54970G>A (p. Gly18324Ser), were detected and segregations were confirmed by polymerase chain reaction-based Sanger sequencing. Conclusions: The compound heterozygous variants, c.61280A>C, (p. Gln20427Pro) and c.54970G>A, (p. Gly18324Ser) in the TTN gene appear to be the cause of Salih myopathy and dilated cardiomyopathy in the family presented. Whole-exome sequencing is an effective molecular diagnostic tool to identify the causative genetic variants of large genes such as TTN.

scholarly journals Whole exome sequencing of a patient with suspected mitochondrial myopathy reveals novel compound heterozygous variants in RYR1

2017 ◽  
Vol 5 (3) ◽  
pp. 295-302 ◽  
Author(s):  
Patrick R. Blackburn ◽  
Duygu Selcen ◽  
Jennifer M. Gass ◽  
Jessica L. Jackson ◽  
Sarah Macklin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Mitochondrial Myopathy ◽  
Compound Heterozygous ◽  
Whole Exome ◽  
Compound Heterozygous Variants

scholarly journals Novel LRPPRC Mutation in a Boy With Mild Leigh Syndrome, French–Canadian Type Outside of Québec

2017 ◽  
Vol 4 ◽  
pp. 2329048X1773763 ◽  
Author(s):  
Velda Xinying Han ◽  
Teresa S. Tan ◽  
Furene S. Wang ◽  
Stacey Kiat-Hong Tay
Keyword(s):  
Cytochrome C ◽  
Exome Sequencing ◽  
Cytochrome C Oxidase ◽  
Whole Exome Sequencing ◽  
Genetic Disorder ◽  
Leigh Syndrome ◽  
Compound Heterozygous ◽  
French Canadian ◽  
Metabolic Crisis ◽  
Whole Exome

Background: Leigh syndrome, French–Canadian type is unique to patients from a genetic isolate in the Saguenay–Lac-Saint-Jean region of Québec. It has also been recently described in 10 patients with LRPPRC mutation outside of Québec. It is an autosomal recessive genetic disorder with fatal metabolic crisis and severe neurological morbidity in infancy caused by LRPPRC mutation. Methods and Results: The authors report a boy with a novel LRPPRC compound heterozygous missense mutations c.3130C>T, c.3430C>T, and c.4078G>A found on whole-exome sequencing which correlated with isolated cytochrome c-oxidase deficiency found in skeletal muscle. Conclusion: LRPPRC mutation is a rare cause of cytochrome c-oxidase–deficient form of Leigh syndrome outside of Québec. Our patient broadens the spectrum of phenotypes of Leigh syndrome, French–Canadian type. LRPPRC mutation should be considered in children with early childhood neurodegenerative disorder, even in the absence of metabolic crisis. Early evaluation with whole-exome sequencing is useful for early diagnosis and for genetic counseling.

scholarly journals Identification of novel pathogenic ABCA4 variants in a Han Chinese family with Stargardt disease

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Qin Xiang ◽  
Yanna Cao ◽  
Hongbo Xu ◽  
Yi Guo ◽  
Zhijian Yang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Retinal Pigment ◽  
Han Chinese ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Stargardt Disease ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Stargardt disease (STGD1, OMIM 248200) is a common hereditary juvenile or early adult onset macular degeneration. It ultimately leads to progressive central vision loss. Here, we sought to identify gene mutations associated with STGD1 in a three-generation Han Chinese pedigree by whole exome sequencing and Sanger sequencing. Two novel potentially pathogenic variants in a compound heterozygous state, c.3607G>T (p.(Gly1203Trp)) and c.6722T>C (p.(Leu2241Pro)), in the ATP binding cassette subfamily A member 4 gene (ABCA4) were identified as contributing to the family’s STGD1 phenotype. These variants may impact the ABCA4 protein structure and reduce the retinal-activated ATPase activity, leading to abnormal all-trans retinal accumulation in photoreceptor outer segments and in retinal pigment epithelium cells. The present study broadens the mutational spectrum of the ABCA4 responsible for STGD1. A combination of whole exome sequencing and Sanger sequencing is likely to be a time-saving and cost-efficient approach to screen pathogenic variants in genetic disorders caused by sizable genes, as well as avoiding misdiagnosis. These results perhaps refine genetic counseling and ABCA4-targetted treatments for families affected by STGD1.

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