Molecular Genetics & Genomic Medicine最新文献

{"title":"Incomplete Trisomy Rescue Reveals the Mechanism Underlying Discordance Between Noninvasive Prenatal Screening and Prenatal Diagnosis.","authors":"Yanan Wang, Yong Zhou, Yuqiong Chai, Weiwei Zang, Hongchao Wang, Fan Yin, Qianqian Tan, Zhigang Chen","doi":"10.1002/mgg3.70091","DOIUrl":"10.1002/mgg3.70091","url":null,"abstract":"<p><strong>Background: </strong>Uniparental disomy (UPD) is a specific type of chromosomal variation in which both chromosomes of a homologous pair are inherited from the same parent. It is responsible for a wide range of disorders. Monosomy rescue and trisomy rescue are the two main hypotheses of UPD generation.</p><p><strong>Methods: </strong>An older parturient woman with a positive noninvasive prenatal screening (NIPS) test but a negative prenatal diagnosis was referred to the hospital. Trio whole exome sequencing (trio-WES) and ddPCR were further performed.</p><p><strong>Results: </strong>Utilizing Trio-WES analysis, our research identified a maternal segmental UPD on chromosome 16, characterized by isodisomic genomic segments at the ends of the chromosome arms and heterodisomic genomic segments near the centromere. Moreover, several nuanced signs pointing to the paternal chromosome 16 were discovered, suggesting a low level of trisomy 16 mosaicism. A homozygous missense mutation (c.1499C>T; p.Ala500Val) was also detected in the fetal TBC1D24 gene, passed down from the heterozygous carrier mother. Furthermore, ddPCR analysis verified a 3% mosaic level of trisomy 16.</p><p><strong>Conclusion: </strong>We have quantitatively verified for the first time a combination of trisomy 16 mosaicism and maternal segmental UPD 16 due to incomplete trisomy rescue, illuminating the cause of the mismatch between positive NIPS and negative prenatal diagnoses.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70091"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625298","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":"Broadening the Phenotype Spectrum of MECP2 Variants in Men.","authors":"Johannes Lötjönen, Venla Kurra, Hannele Laivuori, Nina Bjelogrlić","doi":"10.1002/mgg3.70056","DOIUrl":"10.1002/mgg3.70056","url":null,"abstract":"<p><strong>Background: </strong>MECP2 variants cause X-chromosome-linked rare developmental syndromes. Typically, the mutation is sporadic, occurs in females and is fatal in men. Accurate genetic and clinical diagnostics are considered essential for the management of symptoms and the development of new treatments. These aims may be difficult to reach before more is known about factors resulting in highly variable clinical pictures among patients carrying the same MECP2 variant. We describe the clinical picture of two brothers carrying the same MECP2 variant and compare them with cases published in the literature.</p><p><strong>Methods: </strong>Most of the MECP2 mutations are known to be de novo mutations, which is why the recurrence of the mutation in the couple's other children is unlikely. Unexpectedly, our routine genetic testing revealed a 23-year-old man (P1) and his younger brother (P2) to carry the same hemizygous pathogenic missense variant c.419C>T, p.(Ala140Val) (transcript NM_004992.3) of MECP2, which was found to be inherited from their presumably asymptomatic mother. Thus, further clinical evaluation and comparison with literature cases was considered necessary.</p><p><strong>Results: </strong>The P1 has a severe syndromic intellectual disorder (ID), whereas his brother has a substantially milder ID predominantly limited to problems in verbal skills. Neither P1 nor his younger brother has been diagnosed with Rett syndrome. The P1 (unlike his younger brother) has several lingual, social and motor difficulties; disruptive behavior was the most difficult symptom to treat. P1's response to several medical and non-medical treatment trials has remained inadequate, thus requiring the patient to be hospitalised for a long time. The literature review revealed that apart from our family, there are five other families with more than one male carrying the same MECP2 p.Ala140Val mutation, such as P1 and P2. The phenotypes of all 24 men from us (n = 2) and others (n = 22) carrying the same, presumably non-lethal mutation show great variability.</p><p><strong>Conclusions: </strong>The p.Ala140Val mutation of MECP2 in males is associated with a rare X-chromosomal developmental disorder with highly variable phenotypes. Further studies are needed to better understand all those influencing factors that can explain phenotypic differences within the same genotype to find optimal medicinal therapies.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70056"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066817","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 Novel Variant in TUBB4B Causes Progressive Cone-Rod Dystrophy and Early Onset Sensorineural Hearing Loss.","authors":"Margherita Scarpato, Francesco Testa, Anna Nesti, Roberta Zeuli, Rosa Boccia, Gennaro Auletta, Sandro Banfi, Francesca Simonelli, Marianthi Karali","doi":"10.1002/mgg3.70068","DOIUrl":"10.1002/mgg3.70068","url":null,"abstract":"<p><strong>Background: </strong>Sensorineural hearing loss (SNHL) is a frequent manifestation of syndromic inherited retinal diseases (IRDs), exemplified by the very rare form of autosomal-dominant Leber congenital amaurosis with early onset deafness (LCAEOD; OMIM #617879). LCAEOD was first described in 2017 in four families segregating heterozygous missense mutations in TUBB4B, a gene encoding a β-tubulin isotype. To date, only eight more families with similar TUBB4B-associated sensorineural disease (SND) have been reported. Most cases harbored missense variants affecting the same amino acid (Arg391) and only three families segregated variants involving different residues (Tyr310, Arg390).</p><p><strong>Methods: </strong>We performed whole-exome sequencing and a full ophthalmological and audiological examination of the affected members in an Italian family segregating syndromic IRD with early onset deafness.</p><p><strong>Results: </strong>We identified a novel, ultra-rare, disease-causing variant in TUBB4B (NM_006088.6:c.1049A>C) that replaces a highly conserved lysine with threonine at amino acid position 350. The functional impact of the Lys350Thr substitution was supported by protein structure modeling studies. The variant segregates in the family members presenting retinal disease with early onset SNHL. Detailed ophthalmological assessment of the affected subjects diagnosed a progressive cone-rod dystrophy.</p><p><strong>Conclusion: </strong>These findings expand the limited number of disease-causing TUBB4B variants, corroborating their association with SND forms, and suggest Lys350 is an important residue for β-tubulin function. Interestingly, our results demonstrate that TUBB4B mutations can cause cone-dominated retinal phenotypes.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70068"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059782","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":"Rapid Whole Genome Sequencing Uncovers a Triple Diagnosis: X-Linked Chondrodysplasia Punctata, MECP2-Related Disorder, and Mosaic Jacobs Syndrome.","authors":"Megan Samuels, Kathleen Shields, Paul Hillman, Laura Farach","doi":"10.1002/mgg3.70061","DOIUrl":"10.1002/mgg3.70061","url":null,"abstract":"<p><strong>Background: </strong>Rapid Whole Genome Sequencing (rWGS) is increasingly being used in neonatal intensive care units, as there is growing evidence that rare singe gene disorders present in the neonatal period and early identification can change management. While the diagnostic utility is increased with this broad testing, the possibility of unexpected findings also increases significantly. Here, we present a patient found to have three distinct genetic conditions through rWGS testing, with significant psychosocial and health consequences.</p><p><strong>Methods and results: </strong>This case report describes a patient who was identified with a form of chondrodysplasia punctata, as well as incidental findings of MECP2-related disorder and Jacobs' syndrome. To our knowledge, this is one of the first documented cases of triple genetic diagnoses in the literature, underscoring the expanding clinical utility of rWGS.</p><p><strong>Conclusion: </strong>Our patient represents a unique example of the utility of rWGS in the NICU setting. As two of the three conditions were unexpected results, his case is an important reminder of the possibility of unexpected findings for both providers and families. His case demonstrates the importance of pretest counseling and consenting processes, particularly in an acute setting. It also will add to our understanding of MECP2 variant presentations in males in the future.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70061"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11797297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256264","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":"The First Evidence for the Role of ACVR2A Gene Fetal Genotype in Preeclampsia Susceptibility.","authors":"Asal Honarpour, Ahmad Majd, Hossein Sadeghi, Sayedhamid Jamaldini, Maryam Rahimi, Paniz Kazemzadeh, Reza Mirfakhraie","doi":"10.1002/mgg3.70069","DOIUrl":"10.1002/mgg3.70069","url":null,"abstract":"<p><strong>Background: </strong>The activin A receptor type 2A gene (ACVR2A) plays an important role in normal gestation, particularly in decidualization, trophoblastic invasion, and placentation. Although several studies have investigated the association between ACVR2A maternal variants and preeclampsia (PE) susceptibility; however, controversial results were obtained. Moreover, in none of the previous studies, the role of ACVR2A fetal variants was explored. The aim of the present study was to investigate the role of ACVR2A rs1424954 and rs1424941 polymorphisms in PE susceptibility considering the impact of both fetal and maternal genotypes.</p><p><strong>Methods: </strong>For genotyping of ACVR2A rs1424954 and rs1424941, we performed TP-ARMS-PCR on 600 samples, including 400 peripheral blood samples from preeclamptic and normal women and 200 umbilical cord blood samples from each group of pregnant women.</p><p><strong>Results: </strong>Regarding rs1424954, only the fetal genotypes were associated with an increased risk of PE in both dominant and recessive inheritance models (OR = 2.88, 95% CI: 1.58-5.25, p = 0.0005; and OR = 2.43, 95% CI: 1.21-4.87, p = 0.012; respectively). For ACVR2A rs1424941variant, both maternal and fetal heterozygote genotypes were associated with PE susceptibility (OR = 1.57, 95% CI: 1.02-2.04, p = 0.04; and OR = 1.90, 95% CI: 1.02-3.54, p = 0.04; respectively).</p><p><strong>Conclusion: </strong>The present study confirmed the role of fetal ACVR2A polymorphisms in PE pathogenesis for the first time. However, replicated studies in diverse ethnicities are necessary to confirm the role of fetal genotype on susceptibility to PE.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70069"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080667","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":"Reevaluation of the Impact of the Novel Likely Pathogenic Variant c.1286_1288delAGA in the ATP8A2 Gene: A 7-Year Follow-Up With Clinical, Genetic, and ACMG Insights in an Iranian Family.","authors":"Samira Kalayinia, Hamed Hesami, Reza Shervin Badv, Maryam Rabbani, Zahra Rezaei, Zohreh Hosseinkhani, Sedighe Nikbakht, Ameneh Sharifi, Bahman Akbari, Siamak Mirab Samiee, Nejat Mahdieh","doi":"10.1002/mgg3.70081","DOIUrl":"10.1002/mgg3.70081","url":null,"abstract":"<p><strong>Background: </strong>Cerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare neurodevelopmental disorder characterized by non-progressive cerebellar ataxia, intellectual disability, and cerebellar atrophy. Despite its rarity, CAMRQ syndrome poses significant challenges due to its heterogeneous genetic etiology and complex clinical presentation. This study details the evolving clinical phenotype over 7 years in a male with CAMRQ4 syndrome caused by an in-frame deletion variant in ATP8A2 gene.</p><p><strong>Methods: </strong>A detailed clinical evaluation was performed, accompanied by tests and imaging studies. Clinical and genetic investigations, including segregation analysis, were carried out to confirm the pathogenicity of the identified variant. The evolving clinical phenotype of the patient, including developmental delay, cerebellar ataxia, and hand-foot crawling, was thoroughly investigated.</p><p><strong>Results: </strong>A 10-year-old male patient with CAMRQ syndrome exhibited typical clinical manifestations including impaired motor coordination, cognitive impairment, and balance disturbances. Genetic analysis revealed a homozygous in-frame deletion variant (c.1286_1288delAGA) in the ATP8A2 gene, implicating ATP8A2 in the pathogenesis of CAMRQ syndrome. This variant was predicted to be likely pathogenic and deleterious, in accordance with its segregation in affected family members. Our findings expand the mutational spectrum of ATP8A2-associated CAMRQ syndrome and underscore the importance of comprehensive genetic testing in diagnosing rare neurological disorders.</p><p><strong>Conclusion: </strong>The identification of an in-frame deletion variant in the ATP8A2 gene enhances our understanding of CAMRQ syndrome and highlights the phenotypic variability of the disorder. Our study contributes to the elucidation of CAMRQ syndrome by identifying a novel genetic variant and elucidating its clinical and genetic implications. Further research is warranted to advance our understanding of CAMRQ syndrome and to improve patient care and management strategies.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70081"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391306","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":"Unraveling the Genetic Landscape of Hearing Loss: A Comprehensive Study of Azeri Families in Ardabil, Iran.","authors":"Marzieh Mohseni, Farzane Zare Ashrafi, Ehsan Abbaspour Rodbaneh, Haleh Mokabber, Maryam Vafaei, Ramiz Nobakht, Fatemeh Keshavarzi, Sanaz Arzhangi, Sara Arish, Zahra Nematollahi Azar, Kimia Kahrizi, Hossein Najmabadi, Behzad Davarnia","doi":"10.1002/mgg3.70080","DOIUrl":"10.1002/mgg3.70080","url":null,"abstract":"<p><strong>Background: </strong>Hereditary hearing loss (HHL) is a clinically and genetically heterogeneous sensorineural disorder that presents challenges for diagnosis. Next-generation sequencing (NGS) approaches have facilitated a more cost-effective, streamlined diagnostic process. This study aimed to identify HHL variants using NGS in Iranian Azeri families in Ardabil Province, establishing a suitable framework for screening programs tailored to the local population.</p><p><strong>Methods: </strong>Seventy-four GJB2-negative Azeri families with HHL from Ardabil Province of Iran were studied using the OtoSCOPE panel and/or exome sequencing over 15-years from 2008 to 2023.</p><p><strong>Results: </strong>Data analysis revealed 53 HHL variants in 52 of the 74 most consanguineous families (70%), including 34 pathogenic/likely pathogenic variants and 19 variants of uncertain significance. Seventeen of the detected variants were novel. SLC26A4, MYO7A, USH2A, and TMPRSS3 were the most prevalent mutated genes for non-syndromic hearing loss (NSHL) and syndromic hearing loss (SHL) in this study.</p><p><strong>Conclusion: </strong>Our results are comparable to those of previous studies, indicating that SLC26A4 is the second most common cause of HHL, after GJB2. Moreover, our study emphasizes the significance of understanding the genetic basis of HL for early diagnosis and the implementation of suitable screening programs for various ethnicities in Iran.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70080"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11836346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449564","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":"Trichothiodystrophy due to ERCC2 Variants: Uncommon Contributor to Progressive Hypomyelinating Leukodystrophy.","authors":"Ali Reza Tavasoli, Arastoo Kaki, Maedeh Ganji, Seyyed Mohammad Kahani, Foozhan Radmehr, Pouria Mohammadi, Morteza Heidari, Mahmoud Reza Ashrafi, Kara S Lewis","doi":"10.1002/mgg3.70067","DOIUrl":"10.1002/mgg3.70067","url":null,"abstract":"<p><strong>Background: </strong>Trichothiodystrophy (TTD) is caused by homozygous or compound heterozygous variants in genes associated with DNA repair. The ERCC2 gene encoded a protein, XPD, that is a subunit of the general transcription factor TFIIH and important in both DNA repair and transcription. Disease-causing variants in ERCC2 can partially inactivate these activities, giving rise to symptoms seen in TTD, Cockayne syndrome (CS) and xeroderma pigmentosa (XP). Although generalized cerebral white matter abnormalities is reported in TTD, myelination disorders specifically linked to ERCC2 gene variants are exceptionally uncommon. Here, we introduce a thorough investigation of a patient exhibiting classic TTD symptoms alongside progressive cerebral hypomyelination with ERCC2 variants.</p><p><strong>Methods: </strong>In a non-consanguineous family, we conducted Autism/ID gene Panel on a 5-year-old affected child who presented with microcephaly, failure to thrive, developmental delay, and progressive hypomyelination on three serial brain imaging over 5-years follow-up. Our investigation aimed to elucidate the genetic underpinnings of the observed phenotype. We also conducted a comprehensive review of the genetic profiles of all documented ERCC2-related patients exhibiting myelination disorders.</p><p><strong>Results: </strong>Autism/ID gene Panel identified a compound heterozygous variant in ERCC2 gene causing TTD. Clinical and paraclinical findings enabled differentiation of TTD from Cockayne syndrome and XP. Segregation analysis revealed that, the variation in the paternal allele was a splice junction loss (c.2190 + 1delG), and the other alteration in the maternal allele was a pathogenic variant (c.1479 + 2dupT). It has been noted that these variants were reported in previous studies in homozygous or compound heterozygous form in patients with TTD, but none of them exhibited hypomyelinating leukodystrophy.</p><p><strong>Conclusion: </strong>The identification of hypomyelination in TTD due to ERCC2 sheds a light on the molecular diagnosis and contributing to the limited literature on ERCC2 variants and associated hypomyelinating leukodystrophy in patients with TTD.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70067"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458659","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":"Unmasking a Recessive Allele by a Rare Interstitial Deletion at 10q26.13q26.2: Prenatal Diagnosis of MMP21 -Related Disorder and Further Refine INSYN2A Involvement in the Postnatal Cognitive Phenotype.","authors":"Jiasun Su, Shujie Zhang, Wei Li, Yuan Wei, Fei Lin, Chaofan Zhou, Xianglian Tang, Yueyun Lan, Minpan Huang, Qiang Zhang, Shang Yi, Qi Yang, Sheng Yi, Xunzhao Zhou, Zailong Qin, Peng Huang","doi":"10.1002/mgg3.70082","DOIUrl":"10.1002/mgg3.70082","url":null,"abstract":"<p><strong>Background: </strong>The 10q26 microdeletion syndrome (OMIM #609625) is a distinct genomic disorder characterized by a spectrum of clinical features including craniofacial anomalies, developmental delay (DD)/intellectual disability (ID), hypotonia, cardiovascular, and urogenital malformations. Despite the identification of critical regions within 10q26 linked to the syndrome's phenotype, the specific genes responsible for the associated facial characteristics, microcephaly, cognitive issues, and growth deficiencies remain elusive. Interstitial deletions at 10q25.3-q26.3 are rare, and their contributions to 10q26 microdeletion syndrome remain unknown.</p><p><strong>Methods: </strong>We conducted trio-whole-exome sequencing (WES) on a fetus presenting with ventricular septal defect (VSD), aortic span, intrauterine growth retardation (IUGR), and microcephaly. Variant classification was assessed according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, and the causative gene associated with cognitive phenotype was refined by means of smallest regions of overlap (SRO).</p><p><strong>Results: </strong>A homozygous variant c.1544A>G (p.Tyr515Cys) in MMP21 and a large deletion at 10q26.13-q26.2 which unmasked the homozygous mutation were identified in the proband. The maternally inherited 10q26.13q26.2 deletion was classified as likely pathogenic, while the variant c.1544A>G was of uncertain significance (VUS) based on ACMG/AMP criteria. A critical interval of approximately ~500 kb implicating the involving genes DOCK1 and INSYN2A (inhibitory synaptic factor 2A) in the cognitive phenotype of 10q26 microdeletion syndrome was refined.</p><p><strong>Conclusion: </strong>This study introduces a recessive MMP21 mutation unmasked by a rare 10q26.13q26.2 deletion via WES in a Chinese fetus with congenital heart disease (CHD), IUGR, and microcephaly. We further refine INSYN2A as a potential candidate gene for cognitive phenotype in 10q26.1-q26.3 region. Our study also highlights the utility of WES for its advantage in simultaneously analyzing both single nucleotide variants (SNVs) and copy number variants (CNVs) and provide a reference for prenatal diagnosis and genetic counseling in patients with similar conditions.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70082"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458677","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 Novel Compound Heterozygous Variant in the ABHD12 Gene Cause PHARC Syndrome in a Chinese Family: The Proband Presenting New Genotype and Phenotype.","authors":"Meijiao Ma, Jinhai Ma, Yuanyuan Lian, Xueli Wu, Wenming Wang, Weining Rong, Xunlun Sheng","doi":"10.1002/mgg3.70055","DOIUrl":"10.1002/mgg3.70055","url":null,"abstract":"<p><strong>Background: </strong>PHARC syndrome, a rare autosomal recessive neurodegenerative disorder caused by mutations in the ABHD12 gene, is characterized by demyelinating polyneuropathy, hearing loss, ataxia, retinitis pigmentosa (RP), and early-onset cataracts. If patients are first diagnosed in the ophthalmology department, they are easily misdiagnosed as having RP or Usher syndrome. This study aimed to identify the genetic etiology and determine the clinical diagnosis of a Chinese family with suspected PHARC syndrome.</p><p><strong>Method: </strong>Comprehensive ophthalmic examinations and systemic evaluations were conducted to confirm the phenotype. The genotype was identified through Whole Exome Sequencing (WES), and the current literature was reviewed understand better manifestations of PHARC syndrome related to pathogenic variants.</p><p><strong>Results: </strong>The principal symptoms of the proband comprised profound sensorineural hearing loss since childhood, severe visual impairment, congenital cataracts, cone-rod dystrophy, and ataxia. WES revealed that the proband carried a compound heterozygous variant in the ABHD12 gene: M1, a known nonsense variation c.477G > A (p.Trp159Ter); and M2, a novel copy number variant with a deletion of approximately 18.10 Kbp in chromosome 20p11.21 (seq[GRCh38]del(20) (p11.21)chr20:g. 25302218_25320318del), covering exons 4-12 of the ABHD12 gene. The literature review indicated that there were 65 patients with PHARC from 30 different families. All clinical information of the described patients with PHARC syndrome and all known mutations associated with the disease to date were compiled.</p><p><strong>Conclusion: </strong>This study expands the spectrum of pathogenic variants and phenotype for PHARC syndrome and suggests genetic testing is necessary for a definitive diagnosis of PHARC syndrome.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70055"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256263","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}