Genotype to Phenotype: Identification of Mucopolysaccharidosis Type IIIB (Sanfilippo's B) Case Using Whole Exome Sequencing

AbstractMucopolysaccharidosis type IIIB (Sanfilippo's B; OMIM no.: 252920) is a lysosomal storage disorder caused by defective degradation of heparan sulfate. The enzyme that has decreased function in this disease is α-N acetylglucosaminidase. This enzyme is encoded by the NAGLU gene. A 9-year-old male patient was referred to us with speech disability, developmental delay, hepatomegaly, mild learning disability, and otitis media with effusion complaints. Whole exome sequencing (WES) was performed because of consanguinity between the parents of the patient and the lack of specific prediagnosis. As a result of the patient's WES analysis, a homozygous mutation was detected in the NAGLU gene. The leukocyte enzyme activity was then evaluated to confirm the diagnosis. Alpha-N acetylglucosaminidase deficiency was found. Alpha-N acetylglucosaminidase activity was 0.2 nmol/mLh. WES is a successful diagnostic method in the diagnosis of the mild clinical diseases with recessive inheritance. In addition, our case is a good example of genotype to phenotype diagnosis. Because in storage diseases, the diagnosis is made by leukocyte enzyme analysis first, and then the result is confirmed by gene analysis. The opposite situation occurred in our case.

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Whole-exome sequencing reveals a novel homozygous mutation in the COQ8B gene associated with nephrotic syndrome

Scientific Reports ◽

10.1038/s41598-021-92023-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mohd Fareed ◽

Vikas Makkar ◽

Ravi Angral ◽

Mohammad Afzal ◽

Gurdarshan Singh

Keyword(s):

Nephrotic Syndrome ◽

Disease Management ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Homozygous Mutation ◽

Consanguineous Family ◽

Clinical Prognosis ◽

Whole Exome ◽

Recurrent Mutations ◽

Ckd Stage

AbstractNephrotic syndrome arising from monogenic mutations differs substantially from acquired ones in their clinical prognosis, progression, and disease management. Several pathogenic mutations in the COQ8B gene are known to cause nephrotic syndrome. Here, we used the whole-exome sequencing (WES) technology to decipher the genetic cause of nephrotic syndrome (CKD stage-V) in a large affected consanguineous family. Our study exposed a novel missense homozygous mutation NC_000019.9:g.41209497C > T; NM_024876.4:c.748G > A; NP_079152.3:p.(Asp250Asn) in the 9th exon of the COQ8B gene, co-segregated well with the disease phenotype. Our study provides the first insight into this homozygous condition, which has not been previously reported in 1000Genome, ClinVar, ExAC, and genomAD databases. In addition to the pathogenic COQ8B variant, the WES data also revealed some novel and recurrent mutations in the GLA, NUP107, COQ2, COQ6, COQ7 and COQ9 genes. The novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions: SCV001451361.1, SCV001451725.1 and SCV001451724.1. Based on the patient's clinical history and genomic data with in silico validation, we conclude that pathogenic mutation in the COQ8B gene was causing kidney failure in an autosomal recessive manner. We recommend WES technology for genetic testing in such a consanguineous family to not only prevent the future generation, but early detection can help in disease management and therapeutic interventions.

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Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia

Fertility and Sterility ◽

10.1016/j.fertnstert.2015.04.001 ◽

2015 ◽

Vol 104 (2) ◽

pp. 286-291 ◽

Cited By ~ 42

Author(s):

Ranjith Ramasamy ◽

M. Emre Bakırcıoğlu ◽

Cenk Cengiz ◽

Ender Karaca ◽

Jason Scovell ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Homozygous Mutation ◽

Nonobstructive Azoospermia ◽

Whole Exome

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A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

Acta Endocrinologica ◽

10.1530/eje-16-0968 ◽

2017 ◽

Vol 176 (5) ◽

pp. K9-K14 ◽

Cited By ~ 5

Author(s):

Sandrine Caburet ◽

Ronit Beck Fruchter ◽

Bérangère Legois ◽

Marc Fellous ◽

Stavit Shalev ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Polycystic Ovary ◽

Missense Variant ◽

Genetic Alterations ◽

Homozygous Mutation ◽

Gonadotropin Secretion ◽

Whole Exome ◽

A Genome

Context PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. Objective As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. Methods Whole-exome sequencing and Sanger sequencing confirmation. Results Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. Conclusions This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo–pituitary axis may play role in the pathogenesis of PCOS.

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Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis

10.1101/402388 ◽

2018 ◽

Author(s):

Jose Velilla ◽

Michael Mario Marchetti ◽

Agnes Toth-Petroczy ◽

Claire Grosgogeat ◽

Alexis H Bennett ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

In Silico ◽

Muscular Atrophy ◽

Structural Modeling ◽

Recessive Mutation ◽

Homozygous Mutation ◽

Functional Studies ◽

Whole Exome

AbstractObjectiveThe objective of this study is to identify the genetic cause of disease in a congenital form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).MethodsA 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis and diminished lower limb movement. Whole exome sequencing was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.ResultsWhole exome sequencing revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by western blot and immunohistochemical analysis show that p.S94L reduces TRPV4 protein stability because of increased cytotoxicity and therefore involves a gain-of-function mechanism.ConclusionThis study identifies a novel homozygous mutation in TRPV4 as a cause of the recessive form of congenital spinal muscular atrophy and arthrogryposis.

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Understanding What You Have Found: A Family With a Mutation in the LAMA1 Gene With Literature Review

Clinical Medicine Insights Case Reports ◽

10.1177/1179547620948666 ◽

2020 ◽

Vol 13 ◽

pp. 117954762094866

Author(s):

Muhsin Elmas ◽

Basak Gogus ◽

Mustafa Solak

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Imaging Finding ◽

Large Data ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Sequencing Analysis ◽

Recessive Inheritance ◽

Data Generation ◽

Whole Exome

Introduction: Cerebellar dysplasia with cysts (CDC) is an imaging finding which is typically seen with in individuals with dystroglycanopathy. One of the diseases causing this condition is “Poretti-Boltshauser Syndrome; PTBHS” (OMIM #615960). Homozygous or compound heterozygous mutations in the LAMA1 gene cause this disease. Case presentation: 7 years old twin siblings consulted to the medical genetics department because of walking problems and cerebellar examination findings. Management and Outcome: Clinical and radiological findings of the patient suggested a syndrome with recessive inheritance. Whole exome sequencing (WES) test was performed for definitive diagnosis. As a result of the patient’s WES analysis, a homozygous mutation was detected in the LAMA1 gene. Discussion: When determining the inheritance pattern of genetic diseases, if parents have consanquinity, this situation leads us to recessive inheritance diseases. Even if we are not consanquinity, but they say the same village, it is necessary to pay attention to the diseases of the recessive group. Whole exome sequencing analysis results in large amount of data generation. A good clinical evaluation is required to detect the mutation as a result of large data. To understand what we have found, we need to know what we are looking for.

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Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings

Journal of Child Neurology ◽

10.1177/0883073817712588 ◽

2017 ◽

Vol 32 (10) ◽

pp. 867-870 ◽

Cited By ~ 3

Author(s):

Hannah Song ◽

Sina Haeri ◽

Hannes Vogel ◽

Marjo van der Knaap ◽

Keith Van Haren

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Care ◽

Mutation Screening ◽

Medical Decision ◽

Homozygous Mutation ◽

Vitro Fertilization ◽

Whole Exome ◽

The Impact

Objective: We describe 2 male siblings with a severe, prenatal phenotype of vanishing white matter disease and the impact of whole exome sequencing on their diagnosis and clinical care. Methods: The 2 children underwent detailed clinical characterization, through clinical and laboratory testing, as well as prenatal and postnatal imaging. Biobanked blood from the 2 siblings was submitted for whole exome sequencing at Baylor Laboratories. Results: Both male children had abnormal prenatal neuroimaging and suffered precipitous, fatal neurologic decline. Neuropathologic findings included subependymal pseudocysts, microcalcifications, and profound lack of brain myelin and sparing of peripheral nerve myelin. A novel homozygous mutation in the EIF2B3 gene (c.97A>G [p.Lys33Glu]) was found in both children; both parents were heterozygous carriers. The family subsequently conceived a healthy child via in vitro fertilization with preimplantation mutation screening. Conclusion: These histories expand the prenatal phenotype of eIF2b-related disorders and poignantly illustrate the impact that unbiased genomic sequencing can have on the diagnosis and medical decision making for families affected by childhood neurodegenerative disorders.

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Identification of a Homozygous PEX26 Mutation in a Heimler Syndrome Patient

Genes ◽

10.3390/genes12050646 ◽

2021 ◽

Vol 12 (5) ◽

pp. 646

Author(s):

Youn Jung Kim ◽

Yuichi Abe ◽

Young-Jae Kim ◽

Yukio Fujiki ◽

Jung-Wook Kim

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Correct Diagnosis ◽

Molecular Genetic ◽

Chromosome Study ◽

Homozygous Mutation ◽

Sequencing Analysis ◽

Bilateral Cochlear Implants ◽

Recessive Mutations ◽

Whole Exome

This study aimed to identify the molecular genetic etiology of an 8-year-old boy with amelogenesis imperfecta in permanent dentition. Bilateral cochlear implants were placed due to sensorineural hearing loss, and there was no other family member with a similar phenotype. Peripheral blood samples were collected with the understanding and written consent of the participating family members. A constitutional chromosome study was performed for the proband. Genomic DNA was isolated, and whole exome sequencing was performed. A series of bioinformatic analyses were performed with the obtained paired-end sequencing reads, and the variants were filtered and annotated with dbSNP147. There was no abnormality in the constitutional chromosome study. Whole exome sequencing analysis with trio samples identified a homozygous mutation (c.506T>C, p. (Leu169Pro)) in the PEX26 gene. We verified “temperature sensitivity (ts)” of patient-derived Pex26-L169P by expression in pex26 CHO mutant ZP167 cells to determine the effect of the L169P mutation on Pex26 function. The L169P mutation causes a mild ts-cellular phenotype representing the decreased peroxisomal import of catalase. This study supports the finding that the recessive mutations in PEX26 are associated with Heimler syndrome and demonstrates the importance of an early and correct diagnosis.

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Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss

BMC Medical Genomics ◽

10.1186/s12920-021-00871-9 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Guangxian Yang ◽

Yi Yin ◽

Zhiping Tan ◽

Jian Liu ◽

Xicheng Deng ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Chinese Family ◽

Heterozygous Mutation ◽

Homozygous Mutation ◽

Nonsyndromic Hearing Loss ◽

Whole Exome ◽

Renal Malformations

Abstract Background Previous studies have revealed that mutations of Spalt Like Transcription Factor 1 (SALL1) are responsible for Townes-Brocks syndrome (TBS), a rare genetic disorder that is characterized by an imperforate anus, dysplastic ears, thumb malformations and other abnormalities, such as hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. In addition, the protein tyrosine phosphatase receptor type Q (PTPRQ) gene has been identified in nonsyndromic hearing loss patients with autosomal recessive or autosomal dominant inherited patterns. Methods A Chinese family with TBS and hearing loss was enrolled in this study. The proband was a two-month-old girl who suffered from congenital anal atresia with rectal perineal fistula, ventricular septal defect, patent ductus arteriosus, pulmonary hypertension (PH), and finger deformities. The proband’s father also had external ear deformity with deafness, toe deformities and PH, although his anus was normal. Further investigation found that the proband’s mother presented nonsyndromic hearing loss, and the proband’s mother’s parents were consanguine married. Whole-exome sequencing and Sanger sequencing were applied to detect the genetic lesions of TBS and nonsyndromic hearing loss. Results Via whole-exome sequencing and Sanger sequencing of the proband and her mother, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in the proband and her father who presented TBS phenotypes, and we also detected a new homozygous mutation [ENST00000266688: c.1057_1057delC, p. L353SfsX8)] of PTPRQ in the proband’s mother and uncle, who suffered from nonsyndromic hearing loss. Both mutations were located in the conserved sites of the respective protein and were predicted to be deleterious by informatics analysis. Conclusions This study confirmed the diagnosis of TBS at the molecular level and expanded the spectrum of SALL1 mutations and PTPRQ mutations. Our study may contribute to the clinical management and genetic counselling of TBS and hearing loss.

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Whole-Exome Sequencing Reveals a Rare Variant of OTOF Gene Causing Congenital Non-syndromic Hearing Loss Among Large Muslim Families Favoring Consanguinity

Frontiers in Genetics ◽

10.3389/fgene.2021.641925 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mohd Fareed ◽

Varun Sharma ◽

Inderpal Singh ◽

Sayeed Ur Rehman ◽

Gurdarshan Singh ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Disease Risk ◽

New Delhi ◽

Homozygous Mutation ◽

Jammu And Kashmir ◽

Whole Exome ◽

Recurrent Mutations ◽

Syndromic Hearing Loss

Non-syndromic hearing loss (NSHL) is one of the most frequent auditory deficits in humans characterized by high clinical and genetic heterogeneity. Very few studies have reported the relationship between OTOF (Locus: DFNB9) and hereditary hearing loss in India. We aimed to decipher the genetic cause of prelingual NSHL in a large affected Muslim consanguineous families using whole-exome sequencing (WES). The study was performed following the guidelines and regulations of the Indian Council of Medical Research (ICMR), New Delhi. The population was identified from Jammu and Kashmir, the Northernmost part of India. Near about 100 individuals were born deaf-mute in the village of 3,000 inhabitants. A total of 103 individuals (with 52 cases and 51 controls) agreed to participate in this study. Our study revealed a rare non-sense homozygous mutation NC_000002.11:g.2:26702224G>A; NM_001287489.2:c.2122C>T; NP_001274418.1:p.(Arg708∗) in the 18th exon of the OTOF gene. Our study provides the first insight into this homozygous condition, which has not been previously reported in ExAC, 1,000 Genome and genomAD databases. Furthermore, the variant was confirmed in the population cohort (n = 103) using Sanger sequencing. In addition to the pathogenic OTOF variant, the WES data also revealed novel and recurrent mutations in CDH23, GJB2, MYO15A, OTOG, and SLC26A4 genes. The rare pathogenic and the novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions SCV001448680.1, SCV001448682.1 and SCV001448681.1. We conclude that OTOF-related NSHL hearing loss is prevalent in the region due to successive inbreeding in its generations. We recommend premarital genetic testing and genetic counseling strategies to minimize and control the disease risk in future generations.

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Turkish cases of Mabry Syndrome with a novel homozygous mutation in PGAP2 gene

10.21203/rs.3.rs-772787/v1 ◽

2021 ◽

Author(s):

Ayşe Kartal ◽

Sandeep Jaiswar

Keyword(s):

Alkaline Phosphatase ◽

Mental Retardation ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Disorder ◽

Missense Variant ◽

Homozygous Mutation ◽

Elevated Alkaline Phosphatase ◽

Dysmorphic Features ◽

Whole Exome

Abstract Hyperphosphatasia with mental retardation syndrome is a genetic disorder. We report two siblings aged three years and fourteen years who were investigated for global development delays, seizures and dysmorphic features. A novel missense variant, c.1003G>A (p. Ala335 Thr chr11.3,846,572 NM_001256236.1), in PGAP2 gene was identified using whole-exome sequencing. We highlight the significance of elevated alkaline phosphatase in patients with certain dysmorphic features, can lead to the diagnosis of hyperphosphatasia with mental retardation syndrome using exome sequencing.

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