A novel homozygous mutation disrupting the initiation codon in the SLURP1 gene underlies mal de Meleda in a consanguineous family

2016 ◽  
Vol 41 (6) ◽  
pp. 675-679 ◽  
Author(s):  
K. Shah ◽  
A. Nasir ◽  
Irfanullah ◽  
S. Shahzad ◽  
S. Khan ◽  
...  
Keyword(s):  
Initiation Codon ◽  
Homozygous Mutation ◽  
Consanguineous Family ◽  
Mal De Meleda

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

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.

A homozygous mutation in a consanguineous family consolidates the role ofALDH1A3in autosomal recessive microphthalmia

2013 ◽  
Vol 86 (3) ◽  
pp. 276-281 ◽  
Author(s):  
L. Roos ◽  
M. Fang ◽  
C. Dali ◽  
H. Jensen ◽  
N. Christoffersen ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Homozygous Mutation ◽  
Consanguineous Family

scholarly journals Rare autosomal recessive spastic paraplegias

2019 ◽  
pp. 26-35
Author(s):  
Г.Е. Руденская ◽  
В.А. Кадникова ◽  
А.Л. Чухрова ◽  
Т.В. Маркова ◽  
О.П. Рыжкова
Keyword(s):  
Autosomal Recessive ◽  
Clinical Investigation ◽  
Wide Spectrum ◽  
Spastic Paraparesis ◽  
Bioinformatic Analysis ◽  
Homozygous Mutation ◽  
Consanguineous Family ◽  
Behavioral Impairment ◽  
Dna Diagnostics ◽  
Complex Investigation

Актуальность. Наследственные спастические параплегии (НСП) - одна из наиболее гетерогенных групп наследственных нервных болезней, насчитывающая около 80 клинико-генетических форм (SPG) с хронологической нумерацией. Методы высокопроизводительного экзомного секвенирования (MPS) принципиально расширили возможности выделения новых SPG и практической ДНК-диагностики. В ФГБНУ МГНЦ проводится первое в России комплексное клинико-молекулярное исследование НСП на основе MPS и ряда дополнительных методов ДНК-анализа. Группа верифицированных случаев насчитывает 114 семей с 20 различными формами, включая редкие аутосомно-рецессивные (АР) формы, мало известные генетикам и неврологам. Цель: представить первые российские наблюдения редких АР форм: SPG5, SPG26, SPG35 и SPG39, связанных соответственно с генами CYP7B1, B4GALNT1, FA2H и PNPLA6, участвующими в разных звеньях липидного обмена. Методы. Первичная группа включала около 200 российских семей с предварительным клиническим диагнозом НСП или сходных болезней; основная группа: 114 семей с диагностированной формой SPG; материал статьи: 4 семьи. Использованы методы: клинико-генеалогический, кастомная MPS-панель «параплегии» (64 гена); секвенирование по Сэнгеру; мультиплексная-лигаза зависимая амплификация MLPA (выборочно); полноэкзомное секвенирование WES (выборочно); биоинформатический анализ. Результаты: подгруппа АР SPG включила 22 семьи/12 форм. Представленные 4 формы выявлены в единичных семьях. SPG5: подросток 17 лет в русской семье; начало в 15 лет, умеренный спастический парапарез, легкая сопутствующая атаксия. Генотип CYP7B1: ранее описанные мутации с.334С>T (p.Arg112Ter)/c.1190C>T (p.Pro397Leu) у больного и здоровой сестры 8 лет (доклиническая стадия), родители - гетерозиготные носители. SPG26: мальчик 13 лет в неинбредной русской семье; начало в раннем детстве, медленно прогрессирующий спастический парапарез, дизартрия, когнитивные и поведенческие нарушения, нормальная МРТ. Генотип B4GALNT1: новая мутация c.1514G>C (p.Arg505Pro) в гомозиготном состоянии у больного, в гетерозиготном - у родителей. Случай SPG26 - 14-й описанный в мире, гомозиготность по мутации, вызывающей очень редкую форму SPG, в неинбредной русской семье необычна. SPG35: мальчик 5 лет в этнически смешанной семье (мать русская, отец татарско-бурятского происхождения) из Сибири; начало в 4 года, быстро прогрессирующий спастический парапарез без других симптомов, нормальная МРТ. Генотип FA2H: ранее описанная мутация с.805С>T (p.Arg269Cys) и новая мутация c.106C>T (p.Leu36Phe). SPG39: мальчик 10 лет в русско-татарской семье; начало в 5 лет, умеренный спастический парапарез без других симптомов. Генотип PNPLA6: описанная ранее интронная мутация с.199-2A>T / новая мутация c.2033G>A (p.Gly678Asp), родители - гетерозиготные носители. Выводы. НСП у российских больных представлены широким спектром клинико-генетических форм, включая редкие АР SPG в неинбредных русских и в этнически смешанных семьях. Cлучаи SPG5, SPG26, SPG35 и SPG39 - первые российские описания. Из найденных в 4 генах 7 мутаций три ранее не описаны. MPS - метод выбора ДНК-диагностики болезней с выраженной генетической гетерогенностью, таких, как НСП. Objective: hereditary spastic paraplegias (HSP) are a heterogeneous group including about 80 forms: SPGs (Spastic Paraplegia Gene) numbered chronologically. Massive parallel sequencing MPS greatly improved possibilities of new SPGs disclosure and of practical DNA diagnostics. First Russian HSP complex investigation of HSP using MPS is being performed in FSBI PCMG. By now, the group of genetically diagnosed cases numbers 114 families with 20 different SPGs, including rare autosomal recessive forms poorly known to geneticists and neurologists. Aim: to present first Russian cases of rare autosomal recessive (AR) forms: SPG5, SPG26, SPG35, and SPG39. The genes, CYP7B1, B4GALNT1, FA2H, and FA2H correspondingly, are involved in lipid metabolism. Materials: initial group: about 200 Russian families with preliminary clinical diagnosis of HSP or alike disorders; index group: 114 SPG-confirmed families; paper material: the four families. Methods: clinical investigation, genealogical analysis; molecular methods: custom MPS-panel “paraplegias” (63 genes), Sanger sequencing, multiplex ligation-dependent probe amplification MLPA (selectively), whole-exome sequencing WES (selectively); bioinformatic analysis. Results. Subgroup of AR SPG included 22 families/12 forms. SPG5, 26, 35, 39 were detected in single families. SPG5: a 17-year-old youth in a Russian family; onset in 15 years, moderate spastic paraparesis, mild ataxia; CYP7B1 genotype: two earlier reported mutations .334С>T (p.Arg112Ter) и c.1190C>T (p.Pro397Leu) in the patient and in unaffected younger sister (preclinical stage), parents - heterozygous carries. SPG26: a 13-year old boy in a Russian non-consanguineous family; early-childhood onset, slowly progressing paraparesis, dysarthria, cognitive and behavioral impairment; B4GALNT1 genotype: novel homozygous mutation c.1514G>C (p.Arg505Pro) in the boy, heterozygosity in parents; homozygosity for a very rare gene (14th SPG26 world case) in a Russian non-consanguineous family is unusual. SPG35: a 5-year-old boy in a Sibirian ethnically mixed family (Russian mother, father of Tatar-Buryat ethnicity); onset in 4 years, rapidly progressing paraparesis with no other signs, normal MRI; FA2H genotype: reported earlier с.805С>T (p.Arg269Cys) / novel c.106C>T (p.Leu36Phe). SPG39: a 10-year-old boy in a Russian-Tatar family; onset in 5 years, slowly progressing paraparesis with no other signs; PNPLA6 genotype: reported earlier intronic с.199-2A>T novel c.2033G>A (p.Gly678Asp), parents - heterozygous carriers. Conclusions. HSP in Russian patients present a wide spectrum including rare AR SPG in non-consanguineous Russian families and in families of mixed ethnicity. Our SPG5, SPG26, SPG35 and SPG39 cases are first in Russia; of 7 mutations detected in the 4 genes 3 mutations were novel. MPS is method of choice in DNA diagnostics of heterogeneous disorders like HSP.

scholarly journals Two separate functions of NME3 critical for cell survival underlie a neurodegenerative disorder

2018 ◽  
Vol 116 (2) ◽  
pp. 566-574 ◽  
Author(s):  
Chih-Wei Chen ◽  
Hong-Ling Wang ◽  
Ching-Wen Huang ◽  
Chang-Yu Huang ◽  
Wai Keong Lim ◽  
...  
Keyword(s):  
Cell Survival ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Dynamics ◽  
Initiation Codon ◽  
Metabolic Adaptation ◽  
Mitochondrial Outer Membrane ◽  
Homozygous Mutation ◽  
Glucose Starvation ◽  
Wild Type ◽  
Ndp Kinase

We report a patient who presented with congenital hypotonia, hypoventilation, and cerebellar histopathological alterations. Exome analysis revealed a homozygous mutation in the initiation codon of the NME3 gene, which encodes an NDP kinase. The initiation-codon mutation leads to deficiency in NME3 protein expression. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics. Consistently, the patient’s fibroblasts were characterized by a slow rate of mitochondrial dynamics, which was reversed by expression of wild-type or catalytic-dead NME3. Moreover, glucose starvation caused mitochondrial fragmentation and cell death in the patient’s cells. The expression of wild-type and catalytic-dead but not oligomerization-attenuated NME3 restored mitochondrial elongation. However, only wild-type NME3 sustained ATP production and viability. Thus, the separate functions of NME3 in mitochondrial fusion and NDP kinase cooperate in metabolic adaptation for cell survival in response to glucose starvation. Given the critical role of mitochondrial dynamics and energy requirements in neuronal development, the homozygous mutation in NME3 is linked to a fatal mitochondrial neurodegenerative disorder.

Clinical, Molecular, and Computational Analysis Showed a Novel Homozygous Mutation Among the Substrate-Binding Site of ARSA Protein in Consanguineous Family with Late-Infantile MLD

2018 ◽  
Vol 66 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Abir Ben Issa ◽  
Fatma Kammoun Feki ◽  
Marwa Ben Jdila ◽  
Boudour Khabou ◽  
Bochra Ben Rhouma ◽  
...  
Keyword(s):  
Binding Site ◽  
Computational Analysis ◽  
Substrate Binding ◽  
Homozygous Mutation ◽  
Consanguineous Family ◽  
Substrate Binding Site

A Novel Homozygous Mutation in SPTBN2 Leads to Spinocerebellar Ataxia in a Consanguineous Family: Report of a New Infantile-Onset Case and Brief Review of the Literature

2017 ◽  
Vol 17 (3) ◽  
pp. 276-285 ◽  
Author(s):  
Mohammad A. Al-Muhaizea ◽  
Faten AlMutairi ◽  
Rawan Almass ◽  
Safinaz AlHarthi ◽  
Mazhor S. Aldosary ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Homozygous Mutation ◽  
Review Of The Literature ◽  
Consanguineous Family

Mal de Meleda with homozygous mutation p.G86R in SLURP‐1

2020 ◽  
Vol 59 (6) ◽  
pp. 751-754
Author(s):  
Wei‐Xue Jia ◽  
Yuan‐Yuan Zhang ◽  
Ying‐Da Wu ◽  
Wen‐Rui Li ◽  
Ping Cheng ◽  
...  
Keyword(s):  
Homozygous Mutation ◽  
Mal De Meleda

scholarly journals Case Report: Chorea-Acanthocytosis Presents as Epilepsy in a Consanguineous Family With a Nonsense Mutation of in VPS13A

2021 ◽  
Vol 15 ◽  
Author(s):  
Fang-Mei Luo ◽  
Ming-Xing Deng ◽  
Rong Yu ◽  
Lv Liu ◽  
Liang-Liang Fan
Keyword(s):  
Neuropsychiatric Symptoms ◽  
Elevated Serum ◽  
Genetic Diagnosis ◽  
Peripheral Blood Smear ◽  
Homozygous Mutation ◽  
Consanguineous Family ◽  
Prominent Symptom ◽  
Whole Exome ◽  
Serum Biochemical ◽  
Vacuolar Protein

Chorea-Acanthocytosis (ChAc), a rare autosomal recessive inherited neurological disorder, originated from variants in Vacuolar Protein Sorting 13 homolog A (VPS13A) gene. The main symptoms of ChAc contain hyperkinetic movements, seizures, cognitive impairment, neuropsychiatric symptoms, elevated serum biochemical indicators, and acanthocytes detection in peripheral blood smear. Recently, researchers found that epilepsy may be a presenting and prominent symptom of ChAc. Here, we enrolled a consanguineous family with epilepsy and non-coordinated movement. Whole exome sequencing was employed to explore the genetic lesion of the family. After data filtering, co-separation analysis was performed by Sanger sequencing and bioinformatics analysis, the homozygous nonsense variant (NM_033305.2: c.8282C>G, p.S2761X) of VPS13A were identified which could be genetic factor of the patient. No other meaningful mutations were detected. This mutation (p.S2761X) led to a truncated protein in exon 60 of the VPS13A gene, was simultaneously absent in our 200 local control participants. The homozygous mutation (NM_033305.2: c.8282C>G, p.S2761X) of VPS13A may be the first time be identified in ChAc patient with epilepsy. Our study assisted to the diagnosis of ChAc in this patient and contributed to the genetic diagnosis and counseling of families with ChAc presented as epilepsy. Moreover, we further indicated that epilepsy was a crucial phenotype in ChAc patients caused by VPS13A mutations.

scholarly journals A Homozygous Mutation in GPT2 Associated with Nonsyndromic Intellectual Disability in a Consanguineous Family from Costa Rica

2017 ◽  
pp. 59-66 ◽  
Author(s):  
Tanya Lobo-Prada ◽  
Heinrich Sticht ◽  
Sixto Bogantes-Ledezma ◽  
Arif Ekici ◽  
Steffen Uebe ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Costa Rica ◽  
Homozygous Mutation ◽  
Consanguineous Family

A novel ALMS1 homozygous mutation in two Turkish brothers with Alström syndrome

2016 ◽  
Vol 29 (5) ◽  
Author(s):  
Caley Laxer ◽  
Sofia A. Rahman ◽  
Maha Sherif ◽  
Sophia Tahir ◽  
Atilla Cayir ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Novel Mutation ◽  
Autosomal Recessive Disorder ◽  
Homozygous Mutation ◽  
Consanguineous Family ◽  
Complex Phenotype ◽  
Rare Autosomal Recessive Disorder ◽  
Alström Syndrome ◽  
Alstrom Syndrome

AbstractAlström syndrome (AS) is an extremely rare, autosomal recessive disorder characterised by multi-organ features that typically manifest within the first two decades of life. AS is caused by mutations in the Alström syndrome 1 (In the current study, two brothers from a first-cousin consanguineous family presented with a complex phenotype and were suspected of having AS.Both brothers were found to be homozygous for a novel nonsense c.7310C>A (p.S2437X) mutation in exon-8 ofThis particular mutation has never been reported before and confirmed the diagnosis of AS in the patients. Our work identifies a novel mutation in

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