Molecular Genetics & Genomic Medicine最新文献

{"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}

{"title":"The genetic analysis of eight families with hemophilia B in Mongolia: Identification of two novel mutation","authors":"Purevdorj Munkhuu, Munkhtsetseg Bazarragchaa, Purevdorj Ichinkhorloo, Ki‐Young Yoo, Enkh‐Amar Ayush, Ochbadrakh Batjargal, Erdenebayar Namjil, Sarantuya Jav, Erkhembulgan Purevdorj, Sodnomtsogt Lkhagvasuren","doi":"10.1002/mgg3.2495","DOIUrl":"https://doi.org/10.1002/mgg3.2495","url":null,"abstract":"BackgroundThis study aimed to conduct molecular diagnostics among individuals with hemophilia B (HB) and carriers of hemophilia in Mongolia.MethodsEight patients (six severe, two mild) with HB and their 12 female relatives were enrolled from eight families. Sanger sequence was performed for mutation identification. The questionnaire survey was conducted to evaluate carrier symptoms in female relatives.ResultsTwo families had a history of HB. A total of five different variants (c.223C &gt; T; c.344A &gt; G; c.464G &gt; C; c.187_188del; and c.1314_1314delA) were identified in six patients with severe HB. Of these, two (c.187_188del and c.1314_1314delA) were novel. No variant in the entire <jats:italic>F9</jats:italic> was found in two patients with mild HB. Nonsense c.223C &gt; T (p.Arg75*) mutation was detected in two unrelated patients. Carrier testing identified five mothers as carriers, while one younger sister was a non‐carrier. The carrier status of six female relatives of the two mild patients remained undetermined. By questionnaire survey, only one of the five genetically identified carriers displayed noticeable symptoms of being a carrier.ConclusionThe novel variants c.187_188del and c.1314_1314delA can cause severe hemophilia B. This study did not observe a significant association between symptoms and carrier status in the five carriers.","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"26 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267182","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":"Analysis of the Haematological Phenotype and Molecular Characteristics of Rare Abnormal Haemoglobin","authors":"Yanfen Ge, Guansheng Zheng, Luhua Xian, Yanfei Luo, Junru Liu, Ting Lin, Wenhao Cui, Yujing Yang, Huizhuang Shan","doi":"10.1002/mgg3.70012","DOIUrl":"https://doi.org/10.1002/mgg3.70012","url":null,"abstract":"BackgroundHaemoglobinopathy refers to a group of common monogenic inherited conditions associated with variations in the haemoglobin molecule; however, there is relatively limited reporting on abnormal haemoglobinopathy in the Chinese population, especially rare abnormal haemoglobin (Hb). The aim of this study was to explore the clinical characteristics of haemoglobinopathy to supplement data for the epidemiological investigation of Hb variants in Guangdong province of China.MethodsPeripheral blood was collected from five patients (including a family) for Complete blood count, Hb electrophoresis, High‐performance liquid chromatography analysis and degenerative globin body testing. Hb variants were further analysed by PCR and DNA sequencing.ResultsThe research subjects were diagnosed with different types of abnormal Hb. The blood routine of the Hb Fukuyama (HBB:c.232C&gt;T) diagnosed individual showed microcytic hypochromic anaemia, with a lower Hb level (64 g/L), mean corpuscular volume (MCV) of 71.5 fL and mean corpuscular haemoglobin (MCH) of 21.5 pg. Individuals diagnosed with Hb Port Phillip (HBA2:c.275T&gt;C) exhibit a MCH level that is slightly below average, at 26.4 pg. The Hb Saint Etienne (HBB:c.279C&gt;G) diagnosed individual showed macrocytic hypochromic anaemia, and the proband had a low Hb level (116 g/L), MCV of 102.2 fL and MCH of 29.4 pg.ConclusionWe confirmed the presence of Hb Fukuyama (HBB:c.232C&gt;T) in China for the first time. Three rare patients with the Hb Saint Etienne (HBB:c.279C&gt;G) phenotype and one patient with Hb Port Phillip (HBA2:c.275T&gt;C) phenotype were included. Our research enriches the gene mutation map of haemoglobinopathy in Guangdong province and improves the detection system of haemoglobinopathy for population prevention and eugenics.","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"69 1","pages":"e70012"},"PeriodicalIF":2.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142188672","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":"Incorporating Next-Generation Sequencing as a Second-Tier Test for Primary Carnitine Deficiency.","authors":"Yiming Lin, Zhenzhu Zheng, Weihua Lin, Weilin Peng","doi":"10.1002/mgg3.70003","DOIUrl":"10.1002/mgg3.70003","url":null,"abstract":"<p><strong>Background: </strong>Newborn screening (NBS) for primary carnitine deficiency (PCD) has poor performance. This study aimed to evaluate the feasibility of incorporating next-generation sequencing (NGS) as a second-tier PCD test.</p><p><strong>Methods: </strong>Between March and December 2020, 60,070 newborns were screened for inherited metabolic disorders. Newborns with free carnitine (C0) levels below 8.5 μmol/L were selected for second-tier genetic testing.</p><p><strong>Results: </strong>In total, 130 (0.22%) newborns with low C0 levels underwent second-tier genetic testing, 87 (66.92%) had positive genetic testing results, and 30 (23.08%) carried pathogenic variants of the SLC22A5 gene. Six newborns were diagnosed with PCD. The incidence of PCD was approximately 1 in 1:10,012 newborns. The PPV reached 20% after combining with second-tier NGS. Of the eight variants identified in patients with PCD, the three most common variants were c.760C>T (p.Arg254*), c.51C>G (p.Phe17Leu), and c.1400C>G (p.Ser467Cys). The C0 levels of patients with PCD were significantly lower than those of PCD carriers (p = 0.0026) and PCD-negative individuals (p = 0.0005).</p><p><strong>Conclusions: </strong>Our results showed that the PPV reached 20% after combining with second-tier NGS. The MS/MS-based NBS and second-tier NGS combination can effectively reduce the false-positive rate and detect PCD in patients.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"12 9","pages":"e70003"},"PeriodicalIF":1.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11382357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154641","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}