Neurogenetics最新文献

{"title":"A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability.","authors":"Nana Li,&nbsp;Hong Kang,&nbsp;Yanna Zou,&nbsp;Zhen Liu,&nbsp;Ying Deng,&nbsp;Meixian Wang,&nbsp;Lu Li,&nbsp;Hong Qin,&nbsp;Xiaoqiong Qiu,&nbsp;Yanping Wang,&nbsp;Jun Zhu,&nbsp;Mark Agostino,&nbsp;Julian I-T Heng,&nbsp;Ping Yu","doi":"10.1007/s10048-023-00727-7","DOIUrl":"10.1007/s10048-023-00727-7","url":null,"abstract":"<p><p>Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired adaptive behavior and cognitive capacity. High throughput sequencing approaches have revealed the genetic etiologies for 25-50% of ID patients, while inherited genetic mutations were detected in <5% cases. Here, we investigated the genetic cause for non-syndromic ID in a Han Chinese family. Whole genome sequencing was performed on identical twin sisters diagnosed with ID, their respective children, and their asymptomatic parents. Data was filtered for rare variants, and in silico prediction tools were used to establish pathogenic alleles. Candidate mutations were validated by Sanger sequencing. In silico modeling was used to evaluate the mutation's effects on the protein encoded by a candidate coding gene. A novel heterozygous variant in the ZBTB18 gene c.1323C>G (p.His441Gln) was identified. This variant co-segregated with affected individuals in an autosomal dominant pattern and was not detected in asymptomatic family members. Molecular studies reveal that a p.His441Gln substitution disrupts zinc binding within the second zinc finger and disrupts the capacity for ZBTB18 to bind DNA. This is the first report of an inherited ZBTB18 mutation for ID. This study further validates WGS for the accurate molecular diagnosis of ID.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"251-262"},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10268432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and functional study of two de novo variations of CDKL5 gene.","authors":"Yang You,&nbsp;Xinyi Men,&nbsp;Wenjuan Wu,&nbsp;Shan Liu,&nbsp;Xuexin He,&nbsp;Suzhen Sun,&nbsp;Xiuxia Wang,&nbsp;Baoguang Li","doi":"10.1007/s10048-023-00731-x","DOIUrl":"10.1007/s10048-023-00731-x","url":null,"abstract":"<p><p>The cyclin-dependent kinase like 5 (CDKL5) gene variation is X-linked dominant and is associated with type 2 developmental and epileptic encephalopathy (DEE). Although numerous cases of CDKL5 have been reported, there is limited discussion regarding functional verification. We described two children with DEE caused by de novo variations of CDKL5 gene, analyzed their clinical manifestations, and performed genetic testing on their gene variation sites. The two cases presented with tonic seizures followed by epileptic spasms, indicative of refractory epilepsy. Physical examination revealed abnormal facial features, including wide eye distance, low nose base, and high nose bridge. Both cases exhibited developmental disabilities. Cranial magnetic resonance imaging (MRI) showed widening of the bilateral frontotemporal extracerebral space. Genetic testing identified variations at the gene sites c.463 + 4A > G (splicing) and c.1854_1861delCAAAGTGA (p.D618Efs*18). Minigene experiments further confirmed that the intronic variation c.463 + 4A > G (splicing) disrupted splicing, leading to protein truncation. CDKL5 gene variation can lead to DEE, and intron variation site c.463 + 4A > G (splicing) can cause protein truncation, which is a pathogenic variation.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"263-271"},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10004553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adult-onset Alexander disease among patients of Jewish Syrian descent.","authors":"Saar Anis,&nbsp;Tsvia Fay-Karmon,&nbsp;Simon Lassman,&nbsp;Fadi Shbat,&nbsp;Orit Lesman-Segev,&nbsp;Nofar Mor,&nbsp;Ortal Barel,&nbsp;Dan Dominissini,&nbsp;Odelia Chorin,&nbsp;Elon Pras,&nbsp;Lior Greenbaum,&nbsp;Sharon Hassin-Baer","doi":"10.1007/s10048-023-00732-w","DOIUrl":"10.1007/s10048-023-00732-w","url":null,"abstract":"<p><p>Alexander disease (AxD) is a rare autosomal dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acid protein (GFAP) gene. The age of symptoms onset ranges from infancy to adulthood, with variable clinical and radiological manifestations. Adult-onset AxD manifests as a chronic and progressive condition, characterized by bulbar, motor, cerebellar, and other clinical signs and symptoms. Neuroradiological findings typically involve the brainstem and cervical spinal cord. Adult-onset AxD has been described in diverse populations but is rare in Israel. We present a series of patients diagnosed with adult-onset AxD from three families, all of Jewish Syrian descent. Five patients (4 females) were diagnosed with adult-onset AxD due to the heterozygous mutation c.219G > A, p.Met73Ile in GFAP. Age at symptoms onset ranged from 48 to 61 years. Clinical characteristics were typical and involved progressive bulbar and gait disturbance, followed by pyramidal and cerebellar impairment, dysautonomia, and cognitive decline. Imaging findings included medullary and cervical spinal atrophy and mostly infratentorial white matter hyperintensities. A newly recognized cluster of adult-onset AxD in Jews of Syrian origin is presented. This disorder should be considered in differential diagnosis in appropriate circumstances. Genetic counselling for family members is required in order to discuss options for future family planning.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"303-310"},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10511523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: High genetic heterogeneity of leukodystrophies in Iranian children: the first report of Iranian Leukodystrophy Registry.","authors":"Mahmoudreza Ashrafi,&nbsp;Reyhaneh Kameli,&nbsp;Sareh Hosseinpour,&nbsp;Ehsan Razmara,&nbsp;Zahra Zamani,&nbsp;Zahra Rezaei,&nbsp;Raziyeh Mashayekhi,&nbsp;Neda Pak,&nbsp;Mohammad Barzegar,&nbsp;Reza Azizimalamiri,&nbsp;Morteza Rezvani Kashani,&nbsp;Nahideh Khosroshahi,&nbsp;Maryam Rasulinezhad,&nbsp;Morteza Heidari,&nbsp;Man Amanat,&nbsp;Alireza Abdi,&nbsp;Bahram Mohammadi,&nbsp;Mahmoud Mohammadi,&nbsp;Gholam Reza Zamani,&nbsp;Reza Shervin Badv,&nbsp;Abdolmajid Omrani,&nbsp;Sedigheh Nikbakht,&nbsp;Ali Hosseini Bereshneh,&nbsp;Mojtaba Movahedinia,&nbsp;Hossein Farshad Moghaddam,&nbsp;Hossein Shojaaldini Ardakani,&nbsp;Masood Ghahvechi Akbari,&nbsp;Mehran Beiraghi Tousi,&nbsp;Mohammad Vafaee Shahi,&nbsp;Firouzeh Hosseini,&nbsp;Masoud Hassanvand Amouzadeh,&nbsp;Seyed Ahmad Hosseini,&nbsp;Ali Nikkhah,&nbsp;Ali Khajeh,&nbsp;Hooman Alizadeh,&nbsp;Bahram Yarali,&nbsp;Mohammad Rohani,&nbsp;Parviz Karimi,&nbsp;Hadi Montazer Lotf Elahi,&nbsp;Seyyed Mohamad Mahdi Hosseiny,&nbsp;Masoumeh Sadat Sadeghzadeh,&nbsp;Hossein Mohebbi,&nbsp;Maryam Hosseini Moghadam,&nbsp;Hajar Aryan,&nbsp;Hassan Vahidnezhad,&nbsp;Mahdieh Soveizi,&nbsp;Bahareh Rabbani,&nbsp;Ali Rabbani,&nbsp;Nejat Mahdieh,&nbsp;Masoud Garshasbi,&nbsp;Ali Reza Tavasoli","doi":"10.1007/s10048-023-00733-9","DOIUrl":"10.1007/s10048-023-00733-9","url":null,"abstract":"","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"317-318"},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10157296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spastic paraplegia type 76 due to novel CAPN1 mutations: three case reports with literature review.","authors":"Zeyu Zhu,&nbsp;Wenzhe Hou,&nbsp;Yuwen Cao,&nbsp;Haoran Zheng,&nbsp;Wotu Tian,&nbsp;Li Cao","doi":"10.1007/s10048-023-00726-8","DOIUrl":"10.1007/s10048-023-00726-8","url":null,"abstract":"<p><p>Spastic paraplegia type 76 (SPG76) is a subtype of hereditary spastic paraplegia (HSP) caused by calpain-1 (CAPN1) mutations. Our study described the phenotypic and genetic characteristics of three families with spastic ataxia due to various CAPN1 mutations and further explored the pathogenesis of the two novel mutations. The three patients were 48, 39, and 48 years old, respectively. Patients 1 and 3 were from consanguineous families, while patient 2 was sporadic. Physical examination showed hypertonia, hyperreflexia, and Babinski signs in the lower limbs. Patients 2 and 3 additionally had dysarthria and depression. CAPN1 mutations were identified by whole-exome sequencing, followed by Sanger sequencing and co-segregation analysis within the family. Functional examination of the newly identified mutations was further explored. Two homozygous mutations were detected in patient 1 (c.213dupG, p.D72Gfs*95) and patient 3 (c.1729+1G>A) with HSP, respectively. Patient 2 had compound heterozygous mutations c.853C>T (p.R285X) and c.1324G>A (p.G442S). Western blotting revealed the p.D72Gfs*95 with a smaller molecular weight than WT and p.G442S. In vitro, the wild-type calpain-1 is mostly located in the cytoplasm and colocalized with tubulin by immunostaining. However, p.D72Gfs*95 and p.G442S abnormally formed intracellular aggregation, with little colocalization with tubulin. In this study, we identified three cases with SPG76, due to four various CAPN1 mutations, presenting lower limb spasticity and ataxia, with or without bulbar involvement and emotional disorder. Among these, c.213dupG and c.1324G>A are first identified in this paper. The genotype-phenotype correlation of the SPG76 cases reported worldwide was further summarized.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"243-250"},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9892649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A biallelic loss-of-function variant in TMEM147 causes profound intellectual disability and spasticity.","authors":"Tahereh Ghorashi, Hossein Darvish, Somayeh Bakhtiari, Abbas Tafakhori, Michael C Kruer, Hossein Mozdarani","doi":"10.1007/s10048-023-00734-8","DOIUrl":"10.1007/s10048-023-00734-8","url":null,"abstract":"<p><p>Intellectual disability (ID), occurring in syndromic or non-syndromic forms, is the most common neurodevelopmental disorder. Although many cases are caused by single gene defects, ID is highly genetically heterogeneous. Biallelic variants in the transmembrane protein TMEM147 have recently been linked to intellectual disability with dysmorphic facial features. TMEM147 is believed to localize to the endoplasmic reticulum membrane and nuclear envelope and also involved in biogenesis of multi-pass membrane proteins. Here, we report two patients born to a consanguineous family with a novel loss-of-function variant; (NM_001242597.2:c.193-197del) in TMEM147 causing intellectual disability and spasticity. Whole exome sequencing and validating Sanger sequencing were utilized to confirm the identified causal variant. Our findings were in line with the previously described patients with TMEM147 variants manifesting intellectual disability as a major clinical sign but also featured spasticity as a phenotypic expansion. This study provides additional evidence for the pathogenicity of TMEM147 mutations in intellectual disability and expands the phenotypic and variant spectrum linked to this gene.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"311-316"},"PeriodicalIF":1.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10283824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare PMP22 variants in mild to severe neuropathy uncorrelated to plasma GDF15 or neurofilament light.","authors":"Edouard Palu,&nbsp;Julius Järvilehto,&nbsp;Jana Pennonen,&nbsp;Nadine Huber,&nbsp;Sanna-Kaisa Herukka,&nbsp;Annakaisa Haapasalo,&nbsp;Pirjo Isohanni,&nbsp;Henna Tyynismaa,&nbsp;Mari Auranen,&nbsp;Emil Ylikallio","doi":"10.1007/s10048-023-00729-5","DOIUrl":"10.1007/s10048-023-00729-5","url":null,"abstract":"<p><p>Charcot-Marie-Tooth disease (CMT) is a heterogeneous set of hereditary neuropathies whose genetic causes are not fully understood. Here, we characterize three previously unknown variants in PMP22 and assess their effect on the recently described potential CMT biomarkers' growth differentiation factor 15 (GDF15) and neurofilament light (NFL): first, a heterozygous PMP22 c.178G > A (p.Glu60Lys) in one mother-son pair with adult-onset mild axonal neuropathy. The variant led to abnormal splicing, confirmed in fibroblasts by reverse transcription PCR. Second, a de novo PMP22 c.35A > C (p.His12Pro), and third, a heterozygous 3.2 kb deletion predicting loss of exon 4. The latter two had severe CMT and ultrasonography showing strong nerve enlargement similar to a previous case of exon 4 loss due to a larger deletion. We further studied patients with PMP22 duplication (CMT1A) finding slightly elevated plasma NFL, as measured by the single molecule array immunoassay (SIMOA). In addition, plasma GDF15, as measured by ELISA, correlated with symptom severity for CMT1A. However, in the severely affected individuals with PMP22 exon 4 deletion or p.His12Pro, these biomarkers were within the range of variability of CMT1A and controls, although they had more pronounced nerve hypertrophy. This study adds p.His12Pro and confirms PMP22 exon 4 deletion as causes of severe CMT, whereas the previously unknown splice variant p.Glu60Lys leads to mild axonal neuropathy. Our results suggest that GDF15 and NFL do not distinguish CMT1A from advanced hypertrophic neuropathy caused by rare PMP22 variants.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"291-301"},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10545620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10037767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel potentially pathogenic variants detected in genes causing intellectual disability and epilepsy in Polish families.","authors":"S Skoczylas,&nbsp;P Jakiel,&nbsp;T Płoszaj,&nbsp;K Gadzalska,&nbsp;M Borowiec,&nbsp;A Pastorczak,&nbsp;H Moczulska,&nbsp;M Malarska,&nbsp;A Eckersdorf-Mastalerz,&nbsp;E Budzyńska,&nbsp;A Zmysłowska","doi":"10.1007/s10048-023-00724-w","DOIUrl":"10.1007/s10048-023-00724-w","url":null,"abstract":"<p><strong>Background: </strong>Intellectual disability (ID) affects 1-3% of the world population. The number of genes whose dysfunctions cause intellectual disability is increasing. In addition, new gene associations are constantly being discovered, as well as specific phenotypic features for already identified genetic alterations are being described. The aim of our study was to search for pathogenic variants in genes responsible for moderate to severe intellectual disability and epilepsy, using a panel of targeted next-generation sequencing (tNGS) for diagnosis.</p><p><strong>Methods: </strong>The group of 73 patients (ID, n=32; epilepsy, n=21; ID and epilepsy, n=18) was enrolled in the nucleus DNA (nuDNA) study using a tNGS panel (Agilent Technologies, USA). In addition, high coverage mitochondrial DNA (mtDNA) was extracted from the tNGS data for 54 patients.</p><p><strong>Results: </strong>Fifty-two rare nuDNA variants, as well as 10 rare and 1 novel mtDNA variants, were found in patients in the study group. The 10 most damaging nuDNA variants were subjected to a detailed clinical analysis. Finally, 7 nuDNA and 1 mtDNA were found to be the cause of the disease.</p><p><strong>Conclusions: </strong>This shows that still a very large proportion of patients remain undiagnosed and may require further testing. The reason for the negative results of our analysis may be a non-genetic cause of the observed phenotypes or failure to detect the causative variant in the genome. In addition, the study clearly shows that analysis of the mtDNA genome is clinically relevant, as approximately 1% of patients with ID may have pathogenic variant in mitochondrial DNA.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"221-229"},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10545623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9742843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High genetic heterogeneity of leukodystrophies in Iranian children: the first report of Iranian Leukodystrophy Registry.","authors":"Mahmoudreza Ashrafi,&nbsp;Reyhaneh Kameli,&nbsp;Sareh Hosseinpour,&nbsp;Ehsan Razmara,&nbsp;Zahra Zamani,&nbsp;Zahra Rezaei,&nbsp;Raziyeh Mashayekhi,&nbsp;Neda Pak,&nbsp;Mohammad Barzegar,&nbsp;Reza Azizimalamiri,&nbsp;Morteza Rezvani Kashani,&nbsp;Nahideh Khosroshahi,&nbsp;Maryam Rasulinezhad,&nbsp;Morteza Heidari,&nbsp;Man Amanat,&nbsp;Alireza Abdi,&nbsp;Bahram Mohammadi,&nbsp;Mahmoud Mohammadi,&nbsp;Gholam Reza Zamani,&nbsp;Reza Shervin Badv,&nbsp;Abdolmajid Omrani,&nbsp;Sedigheh Nikbakht,&nbsp;Ali Hosseini Bereshneh,&nbsp;Mojtaba Movahedinia,&nbsp;Hossein Farshad Moghaddam,&nbsp;Hossein Shojaaldini Ardakani,&nbsp;Masood Ghahvechi Akbari,&nbsp;Mehran Beiraghi Tousi,&nbsp;Mohammad Vafaee Shahi,&nbsp;Firouzeh Hosseini,&nbsp;Masoud Hassanvand Amouzadeh,&nbsp;Seyed Ahmad Hosseini,&nbsp;Ali Nikkhah,&nbsp;Ali Khajeh,&nbsp;Hooman Alizadeh,&nbsp;Bahram Yarali,&nbsp;Mohammad Rohani,&nbsp;Parviz Karimi,&nbsp;Hadi Montazer Lotf Elahi,&nbsp;Seyyed Mohamad Mahdi Hosseiny,&nbsp;Masoumeh Sadat Sadeghzadeh,&nbsp;Hossein Mohebbi,&nbsp;Maryam Hosseini Moghadam,&nbsp;Hajar Aryan,&nbsp;Hassan Vahidnezhad,&nbsp;Mahdieh Soveizi,&nbsp;Bahareh Rabbani,&nbsp;Ali Rabbani,&nbsp;Nejat Mahdieh,&nbsp;Masoud Garshasbi,&nbsp;Ali Reza Tavasoli","doi":"10.1007/s10048-023-00730-y","DOIUrl":"10.1007/s10048-023-00730-y","url":null,"abstract":"<p><p>Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous system (CNS). This is the first report of the Iranian LD Registry database to describe the clinical, radiological, and genomic data of Persian patients with leukodystrophies. From 2016 to 2019, patients suspicious of LDs were examined followed by a brain magnetic resonance imaging (MRI). A single gene testing or whole-exome sequencing (WES) was used depending on the neuroradiologic phenotypes. In a few cases, the diagnosis was made by metabolic studies. Based on the MRI pattern, diagnosed patients were divided into cohorts A (hypomyelinating LDs) versus cohort B (Other LDs). The most recent LD classification was utilized for classification of diagnosed patients. For novel variants, in silico analyses were performed to verify their pathogenicity. Out of 680 registered patients, 342 completed the diagnostic evaluations. In total, 245 patients met a diagnosis which in turn 24.5% were categorized in cohort A and the remaining in cohort B. Genetic tests revealed causal variants in 228 patients consisting of 213 variants in 110 genes with 78 novel variants. WES and single gene testing identified a causal variant in 65.5% and 34.5% cases, respectively. The total diagnostic rate of WES was 60.7%. Lysosomal disorders (27.3%; GM2-gangliosidosis-9.8%, MLD-6.1%, KD-4.5%), amino and organic acid disorders (17.15%; Canavan disease-4.5%, L-2-HGA-3.6%), mitochondrial leukodystrophies (12.6%), ion and water homeostasis disorders (7.3%; MLC-4.5%), peroxisomal disorders (6.5%; X-ALD-3.6%), and myelin protein disorders (3.6%; PMLD-3.6%) were the most commonly diagnosed disorders. Thirty-seven percent of cases had a pathogenic variant in nine genes (ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, GCDH). This study highlights the most common types as well as the genetic heterogeneity of LDs in Iranian children.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"279-289"},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10140642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel mutations and molecular pathways identified in patients with brain iron accumulation disorders.","authors":"Lianghao Si,&nbsp;Zhanjun Wang,&nbsp;Xu-Ying Li,&nbsp;Yang Song,&nbsp;Tingyan Yao,&nbsp;Erhe Xu,&nbsp;Xianling Wang,&nbsp;Chaodong Wang","doi":"10.1007/s10048-023-00725-9","DOIUrl":"10.1007/s10048-023-00725-9","url":null,"abstract":"<p><p>Brain iron accumulation disorders (BIADs) are a group of diseases characterized by iron overload in deep gray matter nuclei, which is a common feature of neurodegenerative diseases. Although genetic factors have been reported to be one of the etiologies, much more details about the genetic background and molecular mechanism of BIADs remain unclear. This study aimed to illustrate the genetic characteristics of BIADs and clarify their molecular mechanisms. A total of 84 patients with BIADs were recruited from April 2018 to October 2022 at Xuanwu Hospital. Clinical characteristics including family history, consanguineous marriage history, and age at onset (AAO) were collected and assessed by two senior neurologists. Neuroimaging data were conducted for all the patients, including cranial magnetic resonance imaging (MRI) and susceptibility-weighted imaging (SWI). Whole-exome sequencing (WES) and capillary electrophoresis for detecting sequence mutation and trinucleotide repeat expansion, respectively, were conducted on all patients and part of their parents (whose samples were available). Variant pathogenicity was assessed according to the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP). The NBIA and NBIA-like genes with mutations were included for bioinformatic analysis, using Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genome (KEGG). GO annotation and KEGG pathway analysis were performed on Metascape platform. In the 84 patients, 30 (35.7%) were found to carry mutations, among which 20 carried non-dynamic mutations (missense, stop-gained, frameshift, inframe, and exonic deletion) and 10 carried repeat expansion mutations. Compared with sporadic cases, familial cases had more genetic variants (non-dynamic mutation: P=0.025, dynamic mutation: P=0.003). AAO was 27.85±10.42 years in cases with non-dynamic mutations, which was significantly younger than those without mutations (43.13±17.17, t=3.724, P<0.001) and those with repeated expansions (45.40±8.90, t=4.550, P<0.001). Bioinformatic analysis suggested that genes in lipid metabolism, autophagy, mitochondria regulation, and ferroptosis pathways are more likely to be involved in the pathogenesis of BIADs. This study broadens the genetic spectrum of BIADs and has important implications in genetic counselling and clinical diagnosis. Patients diagnosed as BIADs with early AAO and family history are more likely to carry mutations. Bioinformatic analysis provides new insights into the molecular pathogenesis of BIADs, which may shed lights on the therapeutic strategy for neurodegenerative diseases.</p>","PeriodicalId":56106,"journal":{"name":"Neurogenetics","volume":" ","pages":"231-241"},"PeriodicalIF":2.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10156006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}