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.

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

A Case of Congenital Glucose Galactose Malabsorption with a New Mutation in the SLC5A1 Gene

2020 ◽  
Author(s):  
Hasan Akduman ◽  
Dilek Dilli ◽  
Serdar Ceylaner
Keyword(s):  
Mutation Analysis ◽  
Autosomal Recessive ◽  
Glucose Transporter ◽  
Neonatal Period ◽  
Autosomal Recessive Disorder ◽  
Homozygous Mutation ◽  
New Mutation ◽  
Early Neonatal Period ◽  
Sodium Dependent ◽  
Hypernatremic Dehydration

AbstractCongenital glucose-galactose malabsorption (CGGM) is an autosomal recessive disorder originating from an abnormal transporter mechanism in the intestines. It was sourced from a mutation in the SLC5A1 gene, which encodes a sodium-dependent glucose transporter. Here we report a 2-day-old girl with CGGM who presented with severe hypernatremic dehydration due to diarrhea beginning in the first hours of life. Mutation analysis revealed a novel homozygous mutation NM_000343.3 c.127G > A (p.Gly43Arg) in the SLC5A1 gene. Since CGGM can cause fatal diarrhea in the early neonatal period, timely diagnosis of the disease seems to be essential.

Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14

2019 ◽  
Vol 19 (9) ◽  
pp. 683-687 ◽  
Author(s):  
Tawfiq Froukh ◽  
Ammar Hawwari
Keyword(s):  
Strong Evidence ◽  
Autosomal Recessive ◽  
Eye Diseases ◽  
Initial Reaction ◽  
Genetic Contribution ◽  
Loss Of Function ◽  
Consanguineous Family ◽  
Truncated Protein ◽  
Threonine Residue ◽  
Whole Exome

Background: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical. Despite the strong evidence of genetic contribution in KC, the etiology of KC is not understood in most cases. Methods: In this study, we used whole-exome sequencing to identify the genetic cause of KC in two sibs in a consanguineous family. The Homozygous frameshift variant NM_001253826.1:c.60delC;p.Leu21Cysfs*6 was identified in the gene Nacetylgalactosaminyltransferase 14 (GALNT14). The variant does not exist in all public databases neither in our internal exome database. Moreover, no database harbours homozygous loss of function variants in the candidate gene. Result: GALNT14 catalyses the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on target proteins especially Mucins. Conclusion: As alterations of mucin’s glycosylation are linked to a number of eye diseases, we demonstrate in this study an association between the truncated protein GALNT14 and KC.

Neuropathological Alzheimer’s Disease Lesions in Nasu-Hakola Disease with TREM2 Mutation: Atypical Distribution of Neurofibrillary Changes

2021 ◽  
Vol 79 (1) ◽  
pp. 25-30
Author(s):  
Emanuela Maderna ◽  
Silvia Visonà ◽  
Vittorio Bolcato ◽  
Veronica Redaelli ◽  
Paola Caroppo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Autosomal Recessive ◽  
Cerebral Atrophy ◽  
Autosomal Recessive Disorder ◽  
Homozygous Mutation ◽  
Neurofibrillary Changes ◽  
Axonal Spheroids ◽  
Temporal Structures ◽  
Cortical Involvement

Nasu-Hakola disease is a rare autosomal recessive disorder associated to mutations in TREM2 and DAP12 genes, neuropathologically characterized by leukoencephalopathy with axonal spheroids. We report the neuropathologic findings of a 51-year-old female with a homozygous mutation (Q33X) of TREM2 gene. Beside severe cerebral atrophy and hallmarks of Nasu-Hakola disease, significant Alzheimer’s disease lesions were present. Neurofibrillary changes showed an atypical topographic distribution being severe at spots in the neocortex while sparing the mesial temporal structures. Our finding suggests that TREM2 genetic defects may favor Alzheimer’s disease pathology with neurofibrillary changes not following the hierarchical staging of cortical involvement identified by Braak.

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.

Identification of novel locus at chromosome 3p12.3-q13.31 for autosomal recessive intellectual disability in a consanguineous family

2013 ◽  
Vol 85 (4) ◽  
pp. 390-392
Author(s):  
S. Dad ◽  
E. Østergaard ◽  
K.A. Wadt ◽  
J. Lunding ◽  
H. Eiberg ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Consanguineous Family

Atypical Presentation of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency with Developmental Epileptic Encephalopathy

2021 ◽  
Author(s):  
Francesca Marchese ◽  
Elena Faedo ◽  
Maria Stella Vari ◽  
Patrizia Bergonzini ◽  
Michele Iacomino ◽  
...  
Keyword(s):  
Amino Acid ◽  
Autosomal Recessive ◽  
Epileptic Encephalopathy ◽  
Dopa Decarboxylase ◽  
Acid Decarboxylase ◽  
Homozygous Mutation ◽  
Amino Acid Decarboxylase ◽  
Pathogenic Variants ◽  
Neurological Features ◽  
Decarboxylase Deficiency

AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive metabolic disorder resulting from disease-causing pathogenic variants of the dopa decarboxylase (DDC) gene. The neurological features of AADC deficiency include early-onset hypotonia, oculogyric crises, ptosis, dystonia, hypokinesia, impaired development, and autonomic dysfunction. We report a patient with genetically confirmed AADC deficiency presenting with developmental epileptic encephalopathy (DEE). We report a boy with severe intractable epileptic spasms and DEE. The patient was evaluated for cognitive and neurologic impairment. Exome sequencing revealed a homozygous mutation (NM_000790.4:c.121C > A; p.Leu41Met) in the DDC gene. This case expands the clinical spectrum of AADC deficiency and strengthens the association between dopa decarboxylase deficiency and epilepsy. Additional studies are warranted to clarify the mechanisms linking dopa decarboxylase dysfunction to DEE.

scholarly journals A Case of Salt-Wasting Congenital Adrenal Hyperplasia with Triple Homozygous Mutation: Review of Literature

2020 ◽  
Author(s):  
Maria Laura Iezzi ◽  
Gaia Varriale ◽  
Luca Zagaroli ◽  
Stefania Lasorella ◽  
Marco Greco ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Autosomal Recessive ◽  
Homozygous Mutation ◽  
Adrenal Hyperplasia ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Autosomal Recessive Disorders ◽  
Salt Wasting ◽  
21 Hydroxylase Deficiency ◽  
Recessive Disorders

AbstractCongenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency represents a group of autosomal recessive disorders characterized by impaired cortisol production due to altered upstream steroid conversions, subclassified as classic and nonclassic forms. The genotype–phenotype correlation is possible in the most frequent case but not in all. Despite in literature many mutations are known, there is the possibility of finding a new genetic pattern in patients with CAH.

A Novel Homozygous Deletion within the FRY Gene Associated with Nonsyndromic Developmental Delay

2019 ◽  
Vol 159 (1) ◽  
pp. 19-25 ◽  
Author(s):  
Prabakaran Paulraj ◽  
Michelle Bosworth ◽  
Maria Longhurst ◽  
Callie Hornbuckle ◽  
Garrett Gotway ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Autosomal Recessive ◽  
Pediatric Population ◽  
Homozygous Deletion ◽  
Homozygous Mutation ◽  
Biallelic Mutation ◽  
Snp Microarray ◽  
Low Level

The role of autosomal recessive (AR) variants in clinically heterogeneous conditions such as intellectual disability and developmental delay (ID/DD) has been difficult to uncover. Implication of causative pathogenic AR variants often requires investigation within large and consanguineous families, and/or identifying rare biallelic variants in affected individuals. Furthermore, detection of homozygous gene-level copy number variants during first-line genomic microarray testing in the pediatric population is a rare finding. We describe a 6.7-year-old male patient with ID/DD and a novel homozygous deletion involving the FRY gene identified by genomic SNP microarray. This deletion was observed within a large region of homozygosity on the long arm of chromosome 13 and in a background of increased low-level (2.6%) autosomal homozygosity, consistent with a reported common ancestry in the family. FRY encodes a protein that regulates cell cytoskeletal dynamics, functions in chromosomal alignment in mitosis in vitro, and has been shown to function in the nervous system in vivo. Homozygous mutation of FRY has been previously reported in 2 consanguineous families from studies of autosomal recessive ID in Middle Eastern and Northern African populations. This report provides additional supportive evidence that deleterious biallelic mutation of FRY is associated with ID/DD and illustrates the utility of genomic SNP microarray detection of low-level homozygosity.

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