scholarly journals The Genotype and Phenotype Features in a Large Chinese MFN2 Mutation Cohort

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Ma ◽  
Aping Sun ◽  
Yingshuang Zhang ◽  
Dongsheng Fan ◽  
Xiaoxuan Liu
Keyword(s):  
Early Onset ◽  
De Novo ◽  
Axonal Neuropathy ◽  
Age At Onset ◽  
Mainland China ◽  
Foot Drop ◽  
Charcot Marie Tooth Disease ◽  
Abnormal Gait ◽  
Whole Exome ◽  
Genetic Features

Introduction: Charcot–Marie–Tooth disease type 2A (CMT2A) is a group of clinically and genetically heterogeneous disorders, which is mostly caused by mutations of the mitofusin2 (MFN2) gene. As the genotype–phenotype characteristics of CMT2A were still incompletely understood, we further explored the spectrum of CMT2A variants in China and demonstrated their phenotypic diversities.Methods: A total of 402 index patients/families with CMT throughout Mainland China were enrolled in this study. Among them, we analyzed 20 unrelated index cases with CMT2A by Sanger sequencing, next-generation sequencing, or whole-exome sequencing. Detailed clinical and genetic features of CMT2A patients were collected and analyzed. Of note, de novo mutations were not rare in MFN2 gene; we compared the clinical features of patients from the de novo group with those from the non-de novo group.Results: We identified 20 MFN2 variants, occupying 5.0% of CMT. Most patients presented with early onset and moderate phenotype with abnormal gait and foot drop as the main complaints at onset. Pyramidal signs accounts for 31.6% (6/19) in all patients, which is not uncommon. Four novel variants (p.Tyr752*, c.475-2A>G, p.Val99Met, and p.Arg275_Gln276insArg) were identified in the cohort. Besides, de novo variants occupied 35.0% (7/20) in our study with a much earlier age at onset compared with those in the non-de novo group (p = 0.021).Conclusion: Chinese CMT2A is a predominant typical pure CMT2A, with early onset and mild to moderate phenotype. Given the high frequency of de novo MFN2 mutations, genetic study should be considered for patients with early onset and severe idiopathic axonal neuropathy.

De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy

2019 ◽  
Vol 57 (4) ◽  
pp. 283-288 ◽  
Author(s):  
Joohyun Park ◽  
Bianca R Flores ◽  
Katalin Scherer ◽  
Hanna Kuepper ◽  
Mari Rossi ◽  
...  
Keyword(s):  
Early Onset ◽  
Autosomal Recessive ◽  
De Novo ◽  
Brain Mri ◽  
Sensory Neuropathy ◽  
Sensorimotor Neuropathy ◽  
Charcot Marie Tooth Disease ◽  
Functional Characterisation ◽  
Potassium Influx ◽  
Tooth Disease

BackgroundCharcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT.MethodsWe evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes.ResultsWe identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes.ConclusionOur findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

scholarly journals Two Novel De Novo GARS Mutations Cause Early-Onset Axonal Charcot-Marie-Tooth Disease

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0133423 ◽  
Author(s):  
Yi-Chu Liao ◽  
Yo-Tsen Liu ◽  
Pei-Chien Tsai ◽  
Chia-Ching Chang ◽  
Yen-Hua Huang ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

Duchenne Muscular Dystrophy and Early Onset Hypertrophic Cardiomyopathy associated with Mutations in Dystrophin and Hypertrophic Cardiomyopathy-Associated Genes

2020 ◽  
Author(s):  
Liam Aspit ◽  
Noga Arwas ◽  
Aviva Levitas ◽  
Hanna Krymko ◽  
Yoram Etzion ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Hypertrophic Cardiomyopathy ◽  
Muscular Dystrophy ◽  
Early Onset ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Dystrophin Gene ◽  
Whole Exome ◽  
Rare Phenotype ◽  
Muscular Damage

AbstractDuchenne muscular dystrophy (DMD) is a progressive muscular damage disorder caused by mutations in dystrophin gene. Cardiomyopathy may first be evident after 10 years of age and increases in incidence with age. We present a boy diagnosed at 18 months with a rare phenotype of DMD in association with early-onset hypertrophic cardiomyopathy (HCM). The cause of DMD is a deletion of exons 51–54 of dystrophin gene. The cause of HCM was verified by whole exome sequencing. Novel missense variations in two genes: MAP2K5 inherited from the mother and ACTN2 inherited from the father, or de novo. The combination of MAP2K5, ACTN2, and dystrophin mutations, could be causing the HCM in our patient. This is the second patient diagnosed, at relatively young age, with DMD and HCM, with novel variations in genes known to cause HCM. This study demonstrates the need for genetic diagnosis to elucidate the underlying pathology of HCM.

MYT1L mutation in a patient causes intellectual disability and early onset of obesity: a case report and review of the literature

2019 ◽  
Vol 32 (4) ◽  
pp. 409-413 ◽  
Author(s):  
Abeer Al Tuwaijri ◽  
Majid Alfadhel
Keyword(s):  
Intellectual Disability ◽  
Early Onset ◽  
De Novo ◽  
Copy Number Variants ◽  
Speech Delay ◽  
Single Nucleotide Variants ◽  
Genome Wide ◽  
Whole Exome ◽  
Syndromic Obesity ◽  
The Central Nervous System

Abstract Background Obesity has become one of the greatest health risks worldwide. Recently, there was an explosion of information regarding the role of the central nervous system (CNS) in the development of monogenic and syndromic obesity. Case presentation Over the last decade, terminal and interstitial submicroscopic deletions of copy number variants (CNVs) in 2p25.3 and single nucleotide variants (SNVs) in myelin transcription factor 1 like (MYT1L) were detected by genome-wide array analysis and whole exome sequencing (WES) in patients with a nonspecific clinical phenotype that commonly includes intellectual disability (ID), early onset of obesity and speech delay. Here, we report the first Saudi female patient with mild to moderate ID, early onset of obesity and speech delay associated with a de novo pathogenic SNV in the MYT1L gene (c. 1585G>A [Gly529Arg]), which causes an amino acid change from Gly to Arg at position 529 that leads to mental retardation, autosomal dominant 39.

Novel Rare SORL1 Variants in Early-Onset Dementia

2021 ◽  
pp. 1-10
Author(s):  
Anita Korpioja ◽  
Johanna Krüger ◽  
Susanna Koivuluoma ◽  
Katri Pylkäs ◽  
Virpi Moilanen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Early Onset ◽  
Rare Variants ◽  
Late Onset ◽  
Age At Onset ◽  
Early Onset Dementia ◽  
Missense Variants ◽  
Whole Exome ◽  
Increased Risk

Background: Rare variants of SORL1 have been associated with an increased risk of early-onset or late-onset Alzheimer’s disease (AD). However, a lot remains to be clarified about their significance in the pathogenesis of the disease. Objective: To evaluate the role of SORL1 variants among Finnish patients with early-onset AD (EOAD). Methods: The rare SORL1variants were screened in a cohort of 115 Finnish EOAD patients (mean age at onset 58.3 years, range 46–65 years) by using the whole-exome sequencing. Results: We found one novel nonsense variant (p.Gln290 *) and eight missense variants in SORL1. This is the first study reporting the SORL1 variants p.Lys80Arg, p.Ala789Val and p.Arg866Gln in EOAD patients. Furthermore, two of these three missense variants were overrepresented in EOAD patients compared to gnomAD non-neuro Finnish samples. Conclusion: This study strengthens the earlier findings, that the rare variants in SORL1 are associated with EOAD.

scholarly journals Distinct patterns of speech disorder in early-onset and late-onset de-novo Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jan Rusz ◽  
Tereza Tykalová ◽  
Michal Novotný ◽  
Evžen Růžička ◽  
Petr Dušek
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Standard Deviation ◽  
Early Onset ◽  
De Novo ◽  
Late Onset ◽  
Age At Onset ◽  
Distinct Pattern ◽  
Speech Disorder ◽  
Motor Symptom

AbstractSubstantial variability and severity of dysarthric patterns across Parkinson’s disease (PD) patients may reflect distinct phenotypic differences. We aimed to compare patterns of speech disorder in early-onset PD (EOPD) and late-onset PD (LOPD) in drug-naive patients at early stages of disease. Speech samples were acquired from a total of 96 participants, including two subgroups of 24 de-novo PD patients and two subgroups of 24 age- and sex-matched young and old healthy controls. The EOPD group included patients with age at onset below 51 (mean 42.6, standard deviation 6.1) years and LOPD group patients with age at onset above 69 (mean 73.9, standard deviation 3.0) years. Quantitative acoustic vocal assessment of 10 unique speech dimensions related to respiration, phonation, articulation, prosody, and speech timing was performed. Despite similar perceptual dysarthria severity in both PD subgroups, EOPD showed weaker inspirations (p = 0.03), while LOPD was characterized by decreased voice quality (p = 0.02) and imprecise consonant articulation (p = 0.03). In addition, age-independent occurrence of monopitch (p < 0.001), monoloudness (p = 0.008), and articulatory decay (p = 0.04) was observed in both PD subgroups. The worsening of consonant articulation was correlated with the severity of axial gait symptoms (r = 0.38, p = 0.008). Speech abnormalities in EOPD and LOPD share common features but also show phenotype-specific characteristics, likely reflecting the influence of aging on the process of neurodegeneration. The distinct pattern of imprecise consonant articulation can be interpreted as an axial motor symptom of PD.

scholarly journals De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities

2017 ◽  
Vol 3 (5) ◽  
pp. e187 ◽  
Author(s):  
Ewen W. Sommerville ◽  
Charlotte L. Alston ◽  
Angela Pyle ◽  
Langping He ◽  
Gavin Falkous ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Early Onset ◽  
Autosomal Recessive ◽  
De Novo ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Disorder ◽  
Mitochondrial Respiratory Chain ◽  
Missense Change ◽  
Whole Exome ◽  
Generation Sequencing

Objective:To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder.Methods:A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies.Results:After excluding candidate variants for an autosomal recessive mitochondrial disorder, re-evaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous CTBP1 missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo.Conclusions:We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) CTBP1 variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued re-evaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.

scholarly journals Coding mutations inNUS1contribute to Parkinson’s disease

2018 ◽  
Vol 115 (45) ◽  
pp. 11567-11572 ◽  
Author(s):  
Ji-feng Guo ◽  
Lu Zhang ◽  
Kai Li ◽  
Jun-pu Mei ◽  
Jin Xue ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
De Novo ◽  
Dopamine Level ◽  
De Novo Mutations ◽  
Functional Studies ◽  
Whole Exome ◽  
Independent Case ◽  
The Impact

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson’s disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1,NUP98,PPP2CB,PKMYT1,TRIM24,CEP131,CTTNBP2,NUS1,SMPD3,MGRN1,IFI35, andRUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed thatNUS1harbors significantly more rare nonsynonymous variants (P= 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies inDrosophilademonstrated that the loss ofNUS1could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identifyNUS1as a candidate gene for PD.

scholarly journals Infantile-Onset Charcot–Marie–Tooth Disease With Pyramidal Features and White Matter Abnormalities Due to a De novo MORC2 Gene Variant: A Case Report and Brief Review of the Literature

2021 ◽  
Vol 12 ◽  
Author(s):  
Ivana Frongia ◽  
Susanna Rizzi ◽  
Margherita Baga ◽  
Laura Maria Ceteroni ◽  
Carlotta Spagnoli ◽  
...  
Keyword(s):  
White Matter ◽  
Nerve Conduction ◽  
De Novo ◽  
Late Onset ◽  
Axonal Neuropathy ◽  
Childhood And Adolescence ◽  
Gene Variant ◽  
Charcot Marie Tooth ◽  
White Matter Abnormalities ◽  
Charcot Marie Tooth Disease

Background: Charcot–Marie–Tooth (CMT) is the most frequent group of inherited neuropathies and includes several heterogeneous phenotypes. Over 80 causative genes have been described so far. Variants in the microrchidia family CW-type zinc finger 2 (MORC2) gene have been described in several axonal polyneuropathy (CMT2) patients with childhood or adult onset. Occasionally more complex phenotypes with delayed milestones, severe hypotonia, intellectual disability, dystonic postures, pyramidal signs, and neuroimaging abnormalities have been reported.Case Presentation: We report on a patient with a de novo MORC2 gene variant (c.1181A&gt;G p.Tyr394Cys) with a history of developmental delay, axial hypotonia, progressive gait disorder with dystonic features, and intentional tremor. At the age of 8 years, he showed bilateral pyramidal signs (clonus, increased tendon reflexes, and Babinski sign) and bilateral pes cavus. The first neuroimaging performed at the age of 3 years demonstrated white matter abnormalities in the posterior periventricular zone, in the frontal lobes bilaterally and at the midbrain, stable during childhood and adolescence. Nerve conduction studies (NCS) were negative until the age of 15 years, when a sensory axonal neuropathy appeared. The association between pyramidal signs and neuropathy due to the MORC2 gene variant is increasingly being highlighted, although a neuroradiological correlate is evident only in about half of the cases. Longitudinal nerve conduction velocity (NCV) are helpful to identify late-onset features and provide useful information for diagnosis in patients with rare neurogenetic disorders.Conclusions: Characterization of complex neurological disorders is important to delineate the expanding phenotypic spectrum of MORC2-related disease, to confirm if possible the pathogenicity of the variants and to deepen the genotype–phenotype correlation.

scholarly journals Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

2017 ◽  
Vol 114 (16) ◽  
pp. 4219-4224 ◽  
Author(s):  
Zi-Bing Jin ◽  
Jinyu Wu ◽  
Xiu-Feng Huang ◽  
Chun-Yun Feng ◽  
Xue-Bi Cai ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Early Onset ◽  
High Myopia ◽  
De Novo ◽  
De Novo Mutations ◽  
Treatment And Prevention ◽  
Whole Exome ◽  
Screening Study ◽  
Biallelic Mutations ◽  
Genetic Contributions

The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to −6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in as-yet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.

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