Molecular Genetics & Genomic Medicine最新文献

{"title":"Deep Sequencing and Phenotyping in an Australian Tuberous Sclerosis Complex \"No Mutations Identified\" Cohort.","authors":"Clara W T Chung, Adam M Bournazos, Lok Chi Denise Chan, Vanessa Sarkozy, John Lawson, Sean E Kennedy, Sandra T Cooper, Edwin P Kirk, David Mowat","doi":"10.1002/mgg3.70017","DOIUrl":"10.1002/mgg3.70017","url":null,"abstract":"<p><p>Tuberous sclerosis complex (TSC) is a variable multisystem disorder. The \"no mutations identified\" (NMI) group are reportedly phenotypically milder than those with an identified molecular cause, and often have mosaic or intronic variants not detected by standard sequencing methods.</p><p><strong>Methods: </strong>We describe the phenotypes in an Australian TSC NMI group (n = 18) and a molecular testing strategy implementable in a diagnostic laboratory. Massively parallel sequencing (MPS) of the whole genomic regions of TSC1 and TSC2 was performed using DNA extracted from multiple tissue samples per participant.</p><p><strong>Results: </strong>Our study showed that the phenotype in TSC NMI individuals can be similar to those with heterozygous, particularly TSC1, variants. Although neurodevelopmental outcomes can be less severe, the number of organ systems involved was similar to the non-mosaic groups. A diagnostic yield of 72% (13/18) was achieved, with the majority (10/13) being mosaic variants and the remainder heterozygous variants missed on previous testing.</p><p><strong>Conclusion: </strong>Testing DNA from multiple tissue samples allowed for validation of otherwise discarded low-level mosaic variants and detection of mosaic variants by MPS without excessive cost or the need for specialised techniques. Implementing this approach in a diagnostic setting is viable and allows optimal clinical care of patients with NMI TSC.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 10","pages":"e70017"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350297","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":"Atypical Presentation of Congenital Insensitivity to Pain With Anhidrosis Leading to Diagnostic Odyssey.","authors":"Tomoyasu Higashimoto, Martin E Garber, Lauren Hipp, Jenna Damon, Qing Li","doi":"10.1002/mgg3.70027","DOIUrl":"10.1002/mgg3.70027","url":null,"abstract":"<p><strong>Background: </strong>Congenital insensitivity to pain with anhidrosis (CIPA) (OMIM 256800) is a rare autosomal-recessive condition, also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV). The most commonly reported features include anhidrosis, intellectual disability, self-mutilation, febrile episodes, impaired temperature perception, recurrent infections and/or autonomic nervous system impairment. Major joint destruction and joint deformity known as Charcot (neuropathic) joints are also seen in CIPA patients attributed to insensitivity to joint pain.</p><p><strong>Methods: </strong>We present a case of a 46-year-old female affected with CIPA with a known NTRK1 variant and previously unidentified variant. Minigene reporter constructs were generated encompassing the exon 8 to exon 13 of the NTRK1 gene using the reference sequence and one harboring c.1483 + 5G > A variant identified in our proband. Minigene constructs were transfected into HEK293T cells, and the transcript was analysed for splicing to evaluate the effect of this variant in splicing.</p><p><strong>Results: </strong>The patient (46-year-old female) exhibited right ankle joint deformity around 5 years of age. Patient also experienced lumbar compression and knee damage in adulthood. She had undergone a significant number of evaluations without clear diagnosis. Her presentation lacked many of the common clinical presentations of CIPA, and therefore, the focus of her evaluation was directed towards her unexplained joint deformities. Exome sequencing revealed a known pathogenic variant in NTRK1 (c.851 - 33T > A:p.? [Intron 7]) and a novel NTRK1 variant (c.1483 + 5G > A:p.? [Intron 11]), which was later re-classified as likely pathogenic. The patient was started on a biologic disease-modifying anti-rheumatic medication (bDMARD) due to a possible inflammatory etiology of her joint deformity. Molecular diagnosis allowed for modification of her treatment and surveillance strategies. Our minigene splicing assay demonstrated that the presence of the c.1483 + 5G > A variant has a negative effect on splicing, supporting the pathogenicity of this novel variant.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 10","pages":"e70027"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504414","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":"Identification of Pathogenic Copy Number Variants in Mexican Patients With Inherited Retinal Dystrophies Applying an Exome Sequencing Data-Based Read-Depth Approach.","authors":"Gerardo E Fabian-Morales, Vianey Ordoñez-Labastida, Froylan Garcia-Martínez, Luis Montes-Almanza, Juan C Zenteno","doi":"10.1002/mgg3.70019","DOIUrl":"https://doi.org/10.1002/mgg3.70019","url":null,"abstract":"<p><strong>Background: </strong>Retinal dystrophies (RDs) are the most common cause of inherited blindness worldwide and are caused by genetic defects in about 300 different genes. While targeted next-generation sequencing (NGS) has been demonstrated to be a reliable and efficient method to identify RD disease-causing variants, it doesn't routinely identify pathogenic structural variant as copy number variations (CNVs). Targeted NGS-based CNV detection has become a crucial step for RDs molecular diagnosis, particularly in cases without identified causative single nucleotide or Indels variants. Herein, we report the exome sequencing (ES) data-based read-depth bioinformatic analysis in a group of 30 unrelated Mexican RD patients with a negative or inconclusive genetic result after ES.</p><p><strong>Methods: </strong>CNV detection was performed using ExomeDepth software, an R package designed to detect CNVs using exome data. Bioinformatic validation of identified CNVs was conducted through a commercially available CNV caller. All identified candidate pathogenic CNVs were orthogonally verified through quantitative PCR assays.</p><p><strong>Results: </strong>Pathogenic or likely pathogenic CNVs were identified in 6 out of 30 cases (20%), and of them, a definitive molecular diagnosis was reached in 5 cases, for a final diagnostic rate of ~17%. CNV-carrying genes included CLN3 (2 cases), ABCA4 (novel deletion), EYS, and RPGRIP1.</p><p><strong>Conclusions: </strong>Our results indicate that bioinformatic analysis of ES data is a reliable method for pathogenic CNV detection and that it should be incorporated in cases with a negative or inconclusive molecular result after ES.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 10","pages":"e70019"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470298","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":"A Systematic Review Exploring Empirical Pharmacogenomics Research Within Global Indigenous Populations.","authors":"Bushra Farah Nasir, Ritwika Vinayagam, Luciana Massi, Shivashankar H Nagaraj, Maree Toombs, Kym M Rae","doi":"10.1002/mgg3.70018","DOIUrl":"10.1002/mgg3.70018","url":null,"abstract":"<p><strong>Background: </strong>This systematic review aims to highlight the scope of pharmacogenomics research within global Indigenous populations. This review also explores the barriers and facilitators of pharmacogenomics research within this population.</p><p><strong>Methodology: </strong>A systematic review of literature was conducted to identify and present an understanding of current empirical evidence demonstrating the conduct of genomics or pharmacogenomics research within global Indigenous populations (PROSPERO registration: CRD42021257226). Using key search terms, relevant databases were searched for articles published between January 2010 and July 2022. Screening, data extraction, and analysis was conducted using well-defined inclusion criteria. Quality assessment and risk of bias appraisal was conducted using the mixed methods appraisal tool. Indigenous community engagement and participation in genomics research was assessed using the social-ecological framework.</p><p><strong>Results: </strong>From the 427 articles identified, 77 articles met inclusion criteria and underwent full-text screening. Of these, 30 articles were included in the final review, with 16 being quantitative and 14 either qualitative or mixed methods studies. Most studies were conducted with native Indigenous populations from the United States of America (36%). Content analysis revealed that studies either explored genetic variations associated with disease in Indigenous populations (23%) or markers for drug metabolism (30%) or were designed to understand perspectives of genomics research within this population (47%). Perspectives included the exploration of the role of participants in research, benefits or outcomes achieved from participation in genomics research, and levels of Indigenous engagement and participation in genomics research.</p><p><strong>Conclusions: </strong>This review highlights a growing gap in Indigenous genomics research globally. It presents several important considerations from Indigenous participants, identifying how researchers can co-create culturally safe and inclusive design, implementation, analysis, and subsequent outcomes of genomics research involving Indigenous people. Indigenous governance, self-determination and leadership is essential, with researchers required to be responsive to such fundamental partnerships for research to progress.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 10","pages":"e70018"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470295","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":"Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding.","authors":"Ibrahim M Abdelrazek, Alexej Knaus, Behnam Javanmardi, Peter M Krawitz, Denise Horn, Ebtesam M Abdalla, Sheetal Kumar","doi":"10.1002/mgg3.70023","DOIUrl":"https://doi.org/10.1002/mgg3.70023","url":null,"abstract":"<p><strong>Background: </strong>Acromesomelic chondrodysplasias are a rare subgroup of the clinically and genetically heterogeneous osteochondrodysplasias that are characterised by abnormalities in the limb development and short stature. Here, we report a 2-year-old boy, offspring of consanguineous parents, with acromesomelic dysplasia and postaxial polydactyly in which exome sequencing identified a novel homozygous missense variant in BMPR1B. The patient showed skeletal malformation of both hands and feet that included complex brachydactyly with the thumbs most severely affected, postaxial polydactyly of both hands, shortened toes as well as a bilateral hypoplasia of the fibula.</p><p><strong>Methods: </strong>Whole trio exome sequencing was conducted to identify potential genetic variants in the patient.</p><p><strong>Results: </strong>The analysis identified the biallelic variant NM_001203.3:c.821A > G;p.(Gln274Arg) in BMPR1B, a gene encoding bone morphogenetic protein receptor 1B.</p><p><strong>Conclusion: </strong>The skeletal phenotype can be brought in line with the phenotypes of previously reported cases of BMPR1B-associated chondrodysplasias. However, the postaxial polydactyly described here is a novel clinical finding in a BMPR1B-related case; notably, it has previously been reported in other acromesomelic dysplasia cases caused by homozygous pathogenic variants in GDF5-a gene which encodes for growth differentiation factor 5, a high-affinity ligand to BMPR1B.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 10","pages":"e70023"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11497645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504413","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":"Tremor Ataxia With Central Hypomyelation Phenotype Related to a Recurrent POLR3A Mutation in Six Unrelated Tunisian Families.","authors":"Ichraf Kraoua, Maha Jamoussi, Cyrine Drissi, Lilia Kraoua, Séverine Drunat, Hanene Benrhouma, Thouraya Ben Younes, Sonia Nagi, Sonia Abdelhak, Odile Boespflug Tanguy, Ilhem Ben Youssef-Turki, Mediha Trabelsi, Imen Dorboz","doi":"10.1002/mgg3.70007","DOIUrl":"10.1002/mgg3.70007","url":null,"abstract":"<p><strong>Background: </strong>POLIII-related leukodystrophies are a group of recently recognized hereditary white matter diseases with a similar clinical and radiological phenotype. No Tunisian studies have been published about POLIII-related leukodystrophy due to POLR3A variants. The aim of this study was to contribute to the clinical, radiological, and genetic characterization of POLR3A-related leukodystrophy in a Tunisian cohort.</p><p><strong>Methods: </strong>We report six cases of genetically confirmed POLR3A-related leukodystrophy belonging to six unrelated Tunisian families, along with a review of previously published pediatric cases.</p><p><strong>Results: </strong>All patients were born to consanguineous marriages and originated from the North or the Center of Tunisia. Age at onset varied between 15 months and 6 years. The clinical phenotype was similar in all patients with cerebellar ataxia, tremor, and nystagmus being the key features. Brain imaging showed diffuse hypomyelination in all patients with progressive cerebellar atrophy in three patients. Molecular analysis identified the same bi-allelic NM_007055.4:c.2011T>C; p.(Trp671Arg) variant in the POLR3A gene in all patients.</p><p><strong>Conclusion: </strong>We hypothesize a founder effect for the identified variant given its recurrence in six unrelated individuals with a similar clinical phenotype. Given the apparent genetic homogeneity of Tunisian POLR3A patients, the recurrent variant should be directly targeted. This should facilitate diagnosis in index patients, and genetic counseling.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 10","pages":"e70007"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504415","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":"Extremely Low Birth Weight Infant (Gestational Age of 29 Weeks) With Kabuki Syndrome Type I: Case Report and Literature Review.","authors":"Qi Li, Yuzhu Zheng, Xinyuan Guo, Jiang Xue","doi":"10.1002/mgg3.70025","DOIUrl":"10.1002/mgg3.70025","url":null,"abstract":"<p><strong>Background: </strong>This paper aimed to investigate the clinical phenotype of Kabuki syndrome (KS) in premature infants.</p><p><strong>Methods: </strong>This paper presents a case of an extremely low birth weight infant (gestational age 29 weeks) with KS1 caused by a variant in the KMT2D gene. The clinical, pathological, and differential diagnostic findings were comprehensively analyzed. A thorough literature review was also performed to enhance the understanding of KS, revealing its unique features and prognostic significance.</p><p><strong>Results: </strong>The infant was a male with a gestational age of 29 weeks and a birth weight of 850 g. He had intrauterine growth retardation, characterized by cleft palate, sacrococcygeal skin depressions, and recurrent metabolic acidosis. Whole-exome sequencing revealed the c.4267C > T (p.Arg1423Cys) variant in the KMT2D gene, which was absent in his parents. The patient was discharged after 67 days of treatment, and he was followed up to 19 months of corrected gestational age, with growth retardation and expression language delay. Ten previous studies on preterm infants were retrieved, with 10 preterm infants. They all had characteristic facial features, such as long blepharophimosis, sparse and lateral 1/3 eyebrows, and large and prominent/cupped ears. Other manifestations were extrauterine growth delay (7/10), abnormal development of the cardiovascular system (7/10), abnormal development of the nervous system (5/10), and cleft palate (2/10).</p><p><strong>Conclusions: </strong>Kabuki syndrome is a rare hereditary disorder involving multiple organs and systems. Genetic assessment for preterm infants with congenital abnormalities is recommended.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 10","pages":"e70025"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470296","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":"Application of Whole-Exome Sequencing in the Prenatal Diagnosis of Foetuses With Central Nervous System Abnormalities.","authors":"Caiqun Luo, Erya Wen, Yang Liu, Hui Wang, Bei Jia, Liyuan Chen, Xiaoxia Wu, Qian Geng, Huaxuan Wen, Shengli Li, Bingguang Liu, Weiqing Wu, Mei Zhong","doi":"10.1002/mgg3.70016","DOIUrl":"10.1002/mgg3.70016","url":null,"abstract":"<p><strong>Objective: </strong>To investigate the clinical value of whole-exome sequencing (WES) in the diagnosis of foetuses with central nervous system (CNS) abnormalities but having a normal karyotyping and chromosomal microarray result.</p><p><strong>Method: </strong>During the period of 2016-2022, there were a total of 149 foetuses with CNS abnormalities but having negative karyotyping and chromosomal microarray analysis results; WES was performed on these foetuses and their parents. Variants were classified according to ACMG guidelines, and the association of pathogenic variants with specific types of CNS abnormalities was explored.</p><p><strong>Results: </strong>Among these 149 foetuses, three categories of abnormalities, namely, single CNS abnormality, multiple CNS abnormalities, CNS abnormalities along with other organ system abnormalities were identified, for which the detection rate of P/LP variants is 17.4% (12/69), 28.6% (14/49) and 54.8% (17/31), respectively.</p><p><strong>Conclusion: </strong>WES brought about an increase of 28.9% in diagnostic yield in the prenatal evaluation of foetuses with CNS abnormalities but having negative karyotyping and chromosome array results. WES may also be of benefit for the diagnosis of foetuses with isolated CNS abnormalities, as well as for making more informed interpretations of imaging findings and for providing better genetic counselling.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 10","pages":"e70016"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365847","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":"CANVAR: A Tool for Clinical Annotation of Variants Using ClinVar Databases.","authors":"Lau K Vestergaard, Joanna Lopacinska-Jørgensen, Estrid V Høgdall","doi":"10.1002/mgg3.70020","DOIUrl":"10.1002/mgg3.70020","url":null,"abstract":"<p><strong>Background: </strong>Genomic medicine has transformed clinical genetics by utilizing high-throughput sequencing technologies to analyze genetic variants associated with diseases. Accurate variant classification is crucial for diagnosis and treatment decisions, and various tools and software such as the Ion Reporter Software and the Illumina Nirvana Software often used in a clinical setting utilize information from the ClinVar database/archive to aid in variant interpretation. However, these existing annotation tools may lack access to the latest ClinVar data, necessitating manual variant inspection.</p><p><strong>Aims: </strong>To address this gap in developing a tool providing the latest ClinVar data for variant annotation in clinical and research settings.</p><p><strong>Materials and methods: </strong>We introduce CANVAR, a Python-based script that efficiently annotates variants identified from next-generation sequencing in a clinical or research context, offering comprehensive information from the latest ClinVar database.</p><p><strong>Results: </strong>CANVAR provides accurate, up-to-date variant annotations, streamlining variant analysis.</p><p><strong>Discussion: </strong>The rise in genomic data requires accurate variant annotation for clinical decision-making. Misclassification poses risks, and current tools may not always access the latest data, challenging variant interpretation.</p><p><strong>Conclusion: </strong>CANVAR contributes to enhancing variant annotation by offering comprehensive information from the latest ClinVar database for genetic variants identified through next-generation sequencing.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 10","pages":"e70020"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391913","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":"Clinical Characteristics, Genetic Analysis, and Literature Review of Cornelia de Lange Syndrome Type 4 Associated With a RAD21 Variant","authors":"Xinyu Yue, Meiping Chen, Xiaoan Ke, Hongbo Yang, Fengying Gong, Linjie Wang, Lian Duan, Hui Pan, Huijuan Zhu","doi":"10.1002/mgg3.70009","DOIUrl":"https://doi.org/10.1002/mgg3.70009","url":null,"abstract":"BackgroundCornelia de Lange syndrome (CdLS) is an uncommon congenital developmental disorder distinguished by intellectual disorder and distinctive facial characteristics, with a minority of cases attributed to <jats:italic>RAD21</jats:italic> variants.MethodsA patient was admitted to the endocrinology department at Peking Union Medical College Hospital, where 2 mL of peripheral venous blood was collected from the patient and his parents. DNA was extracted for whole‐exome sequencing (WES) analysis, and the genetic variation of the parents was confirmed through Sanger sequencing.ResultsA 13.3‐year‐old male patient with a height of 136.5 cm (−3.5 SDS) and a weight of 28.4 kg (−3.1 SDS) was found to have typical craniofacial features. WES revealed a pathogenic variant c.1143G&gt;A (p.Trp381*) in the <jats:italic>RAD21</jats:italic> gene. He was diagnosed with CdLS type 4 (<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" xlink:href=\"https://www.omim.org/entry/614701?search=614701&amp;highlight=614701\">OMIM #614701</jats:ext-link>). We reviewed 36 patients with CdLS related to <jats:italic>RAD21</jats:italic> gene variants reported worldwide from May 2012 to March 2024. Patient's variant status, clinical characteristics, and rhGH treatment response were summarized. Frameshift variants constituted the predominant variant type, representing 36% (13/36) of cases. Clinical features included verbal developmental delay and intellectual disorder observed in 94% of patients.ConclusionThis study reported the third case of CdLS type 4 in China caused by a <jats:italic>RAD21</jats:italic> gene variant, enriching the genetic mutational spectrum.","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"10 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267184","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}