Genetics in Medicine最新文献

{"title":"Variants in UBAP1L lead to autosomal recessive rod-cone and cone-rod dystrophy","authors":"Christina Zeitz ,&nbsp;Julien Navarro ,&nbsp;Leila Azizzadeh Pormehr ,&nbsp;Cécile Méjécase ,&nbsp;Luiza M. Neves ,&nbsp;Camille Letellier ,&nbsp;Christel Condroyer ,&nbsp;Shahad Albadri ,&nbsp;Andréa Amprou ,&nbsp;Aline Antonio ,&nbsp;Tasnim Ben-Yacoub ,&nbsp;Juliette Wohlschlegel ,&nbsp;Camille Andrieu ,&nbsp;Malo Serafini ,&nbsp;Lorenzo Bianco ,&nbsp;Alessio Antropoli ,&nbsp;Marco Nassisi ,&nbsp;Said El Shamieh ,&nbsp;Sandra Chantot-Bastaraud ,&nbsp;Saddek Mohand-Saïd ,&nbsp;Isabelle Audo","doi":"10.1016/j.gim.2024.101081","DOIUrl":"10.1016/j.gim.2024.101081","url":null,"abstract":"<div><h3>Purpose</h3><p>Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian descent with only few reports of North African descent.</p></div><div><h3>Methods</h3><p>Genome, targeted next-generation, and Sanger sequencing was applied to cohort of ∼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium cells, and zebrafish. Variants’ pathogenicity was accessed using 3D-modeling and/or ROs.</p></div><div><h3>Results</h3><p>Here, we identified a novel gene defect with three distinct pathogenic variants in <em>UBAP1L</em> in 4 independent autosomal recessive IRD cases from Tunisia. <em>UBAP1L</em> is expressed in the retinal pigment epithelium and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin-associated domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the solenoid of overlapping ubiquitin-associated domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein.</p></div><div><h3>Conclusion</h3><p>Biallelic <em>UBAP1L</em> variants are a novel cause of IRDs, most likely enriched in the North African population.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024000145/pdfft?md5=33acc92b25da13257c9c33f4bb9e974a&pid=1-s2.0-S1098360024000145-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139585848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Satisfaction with mode of delivery of genomic sequencing results in a diverse national sample of research participants through the Clinical Sequencing Evidence-Generating Research Consortium","authors":"","doi":"10.1016/j.gim.2024.101176","DOIUrl":"10.1016/j.gim.2024.101176","url":null,"abstract":"<div><h3>Purpose</h3><p>Research that includes diverse patient populations is necessary to optimize implementation of telehealth.</p></div><div><h3>Methods</h3><p>As part of a Clinical Sequencing Evidence-Generating Research Consortium cross-site study, we assessed satisfaction with mode of return of results (RoR) delivery across a diverse sample of participants receiving genetic testing results in person vs telemedicine (TM).</p></div><div><h3>Results</h3><p>Ninety-eight percent of participants were satisfied with their mode of results delivery. Participants receiving results by TM were more likely to report a preference for receiving results in a different way and challenges with providers noticing difficulties with understanding. More than 90% reported satisfaction across all items measuring support and interaction during sessions. Participants self-reporting Hispanic/Latino or Black/African American race and ethnicity compared with White/European American, fewer years of education, and having lower health literacy were more likely to report challenges with understanding the information or asking questions. Participants who were White/European American, had more years of education, and higher health literacy reported higher communication scores, reflecting more positive evaluations of the communication experience.</p></div><div><h3>Conclusion</h3><p>TM is an acceptable mode of return of results delivery across diverse settings and populations. Research optimizing approaches for underrepresented populations, populations with lower levels of education and health literacy, and multilingual populations is necessary.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss-of-function variants in UBAP1L cause autosomal recessive retinal degeneration","authors":"Ji Hoon Han ,&nbsp;Kim Rodenburg ,&nbsp;Tamar Hayman ,&nbsp;Giacomo Calzetti ,&nbsp;Karolina Kaminska ,&nbsp;Mathieu Quinodoz ,&nbsp;Molly Marra ,&nbsp;Sandrine Wallerich ,&nbsp;Gilad Allon ,&nbsp;Zoltán Z. Nagy ,&nbsp;Krisztina Knézy ,&nbsp;Yumei Li ,&nbsp;Rui Chen ,&nbsp;Mirella Telles Salgueiro Barboni ,&nbsp;Paul Yang ,&nbsp;Mark E. Pennesi ,&nbsp;L. Ingeborgh van den Born ,&nbsp;Balázs Varsányi ,&nbsp;Viktória Szabó ,&nbsp;Dror Sharon ,&nbsp;Carlo Rivolta","doi":"10.1016/j.gim.2024.101106","DOIUrl":"10.1016/j.gim.2024.101106","url":null,"abstract":"<div><h3>Purpose</h3><p>Inherited retinal diseases (IRDs) are a group of monogenic conditions that can lead to progressive blindness. Their missing heritability is still considerable, due in part to the presence of disease genes that await molecular identification. The purpose of this work was to identify novel genetic associations with IRDs.</p></div><div><h3>Methods</h3><p>Patients underwent a comprehensive ophthalmological evaluation using standard-of-care tests, such as detailed retinal imaging (macular optical coherence tomography and short-wavelength fundus autofluorescence) and electrophysiological testing. Exome and genome sequencing, as well as computer-assisted data analysis were used for genotyping and detection of DNA variants. A minigene-driven splicing assay was performed to validate the deleterious effects of 1 of such variants.</p></div><div><h3>Results</h3><p>We identified 8 unrelated families from Hungary, the United States, Israel, and The Netherlands with members presenting with a form of autosomal recessive and nonsyndromic retinal degeneration, predominantly described as rod-cone dystrophy but also including cases of cone/cone-rod dystrophy. Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later. Myopia greater than 5 diopters was present in 5 of 7 cases with available refractive data, and retinal detachment was reported in 2 cases. All ascertained patients carried biallelic loss-of-function variants in <em>UBAP1L</em> (HGNC: 40028), a gene with unknown function and with homologies to <em>UBAP1</em>, encoding a protein involved in ubiquitin metabolism. One of these pathogenic variants, the intronic NM_001163692.2:c.910-7G&gt;A substitution, was identified in 5 unrelated families. Minigene-driven splicing assays in HEK293T cells confirmed that this DNA change is responsible for the creation of a new acceptor splice site, resulting in aberrant splicing.</p></div><div><h3>Conclusion</h3><p>We identified <em>UBAP1L</em> as a novel IRD gene. Although its function is currently unknown, <em>UBAP1L</em> is almost exclusively expressed in photoreceptors and the retinal pigment epithelium, hence possibly explaining the link between pathogenic variants in this gene and an ocular phenotype.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S109836002400039X/pdfft?md5=621ec8520a9b6c6b7264e2628b41d9e2&pid=1-s2.0-S109836002400039X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139989799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Where there is no genetic counselor: An online decision-aid supports the majority of parents’ diagnostic genomic testing choices for their children","authors":"","doi":"10.1016/j.gim.2024.101173","DOIUrl":"10.1016/j.gim.2024.101173","url":null,"abstract":"<div><h3>Purpose</h3><p>We evaluated DECIDE, an online pretest decision-support tool for diagnostic genomic testing, in nongenetics specialty clinics where there are no genetic counselors (GCs).</p></div><div><h3>Methods</h3><p>Families of children offered genomic testing were eligible to participate. Fifty-six parents/guardians completed DECIDE at home, at their convenience. DECIDE includes an integrated knowledge quiz and decisional conflict screen. Six months later, parents were offered follow-up questionnaires and interviews about their experiences.</p></div><div><h3>Results</h3><p>Forty parents (71%) had sufficient knowledge and no decisional conflict surrounding their testing decision, but 6 of this group had residual questions. These 6, plus 16 with decisional conflict or insufficient knowledge, saw a GC. At follow-up, little-to-no decisional regret and few negative emotions were identified in any parents. Most chose testing and described their decision as easy, yet stressful, and described many motivations for sequencing. Parents appreciated the simple comprehensive information DECIDE provided and the ability to view it in a low-stress environment.</p></div><div><h3>Conclusion</h3><p>DECIDE provides adequate decision-support to enable most parents to make value-consistent choices about genetic testing for their child. Parents reported that DECIDE helped to clarify motivations for pursuing (or declining) testing. DECIDE is a timely, well-tested, and accessible tool in clinical settings without GCs.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024001072/pdfft?md5=295c92d5816660b084d57a445525f1f1&pid=1-s2.0-S1098360024001072-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer risks for other sites in addition to breast in CHEK2 c.1100delC families","authors":"","doi":"10.1016/j.gim.2024.101171","DOIUrl":"10.1016/j.gim.2024.101171","url":null,"abstract":"<div><h3>Purpose</h3><p>Female <em>CHEK2</em> c.1100delC heterozygotes are eligible for additional breast surveillance because of an increased breast cancer risk. Increased risks for other cancers have been reported. We studied whether <em>CHEK2</em> c.1100delC is associated with an increased risk for other cancers within these families.</p></div><div><h3>Methods</h3><p>Including 10,780 individuals from 609 families, we calculated standardized incidence rates (SIRs) and absolute excess risk (AER, per 10,000 person-years) by comparing first-reported cancer derived from the pedigrees with general Dutch population rates from 1970 onward. Attained-age analyses were performed for sites in which significant increased risks were found. Considering the study design, we primarily focused on cancer risk in women.</p></div><div><h3>Results</h3><p>We found significant increased risks of colorectal cancer (CRC; SIR = 1.43, 95% CI = 1.14-1.76; AER = 1.43) and hematological cancers (SIR = 1.32; 95% CI = 1.02-1.67; AER = 0.87). CRC was significantly more frequent from age 45 onward.</p></div><div><h3>Conclusion</h3><p>A significantly increased risk of CRC, and hematological cancers in women was found, starting at a younger age than expected. Currently, colorectal surveillance starts at age 45 in high-risk individuals. Our results suggest that some <em>CHEK2</em> c.1100delC families might benefit from this surveillance as well; however, further research is needed to determine who may profit from this additional colorectal surveillance.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024001059/pdfft?md5=603223c4dfeb11278274f4445aa213a8&pid=1-s2.0-S1098360024001059-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural history of adults with KBG syndrome: A physician-reported experience","authors":"Allan Bayat ,&nbsp;Hannah Grimes ,&nbsp;Elke de Boer ,&nbsp;Morten Krogh Herlin ,&nbsp;Rebekka Staal Dahl ,&nbsp;Ida Charlotte Bay Lund ,&nbsp;Michael Bayat ,&nbsp;Anneli Clea Skjelmose Bolund ,&nbsp;Cathrine Elisabeth Gjerulfsen ,&nbsp;Pernille Axél Gregersen ,&nbsp;Monica Zilmer ,&nbsp;Stefan Juhl ,&nbsp;Katarzyna Cebula ,&nbsp;Elisa Rahikkala ,&nbsp;Isabelle Maystadt ,&nbsp;Angela Peron ,&nbsp;Aglaia Vignoli ,&nbsp;Rosa Maria Alfano ,&nbsp;Franco Stanzial ,&nbsp;Francesco Benedicenti ,&nbsp;Karen Jaqueline Low","doi":"10.1016/j.gim.2024.101170","DOIUrl":"10.1016/j.gim.2024.101170","url":null,"abstract":"<div><h3>Purpose</h3><p>KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of <em>ANKRD11.</em> The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS.</p></div><div><h3>Methods</h3><p>We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data.</p></div><div><h3>Results</h3><p>The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (<em>n</em> = 22); gross and/or fine motor difficulties (<em>n</em> = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (<em>n</em> = 26); nonverbal (<em>n</em> = 3), seizures with various seizure types and treatment responses (<em>n</em> = 10); ophthalmological comorbidities (<em>n</em> = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (<em>n</em> = 2) and autoimmune conditions (<em>n</em> = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets.</p></div><div><h3>Conclusion</h3><p>Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder","authors":"Khemika K. Sudnawa ,&nbsp;Wenxing Li ,&nbsp;Sean Calamia ,&nbsp;Cara H. Kanner ,&nbsp;Jennifer M. Bain ,&nbsp;Aliaa H. Abdelhakim ,&nbsp;Alexa Geltzeiler ,&nbsp;Caroline M. Mebane ,&nbsp;Frank A. Provenzano ,&nbsp;Tristan T. Sands ,&nbsp;Robert J. Fee ,&nbsp;Jacqueline Montes ,&nbsp;Yufeng Shen ,&nbsp;Wendy K. Chung","doi":"10.1016/j.gim.2024.101169","DOIUrl":"10.1016/j.gim.2024.101169","url":null,"abstract":"<div><h3>Purpose</h3><p>Pathogenic variants in kinesin family member 1A (<em>KIF1A</em>) are associated with <em>KIF1A</em>-associated neurological disorder. We report the clinical phenotypes and correlate genotypes of individuals with <em>KIF1A</em>-associated neurological disorder.</p></div><div><h3>Methods</h3><p>Medical history and adaptive function were assessed longitudinally. In-person evaluations included neurological, motor, ophthalmologic, and cognitive assessments.</p></div><div><h3>Results</h3><p>We collected online data on 177 individuals. Fifty-seven individuals were also assessed in-person. Most individuals had de novo heterozygous missense likely pathogenic/pathogenic <em>KIF1A</em> variants. The most common characteristics were hypotonia, spasticity, ataxia, seizures, optic nerve atrophy, cerebellar atrophy, and cognitive impairment. Mean Vineland adaptive behavior composite score (VABS-ABC) was low (M = 62.9, SD = 19.1). The mean change in VABS-ABC over time was −3.1 (SD = 7.3). The decline in VABS-ABC was associated with the age at first assessment and abnormal electroencephalogram/seizure. There was a positive correlation between evolutionary scale model (ESM) score for the variants and final VABS-ABC (<em>P</em> = .003). Abnormal electroencephalogram/seizure, neuroimaging result, and ESM explain 34% of the variance in final VABS-ABC (<em>P</em> &lt; .001).</p></div><div><h3>Conclusion</h3><p>In-person assessment confirmed caregiver report and identified additional visual deficits. Adaptive function declined over time consistent with both the neurodevelopmental and neurodegenerative nature of the condition. Using ESM score assists in predicting phenotype across a wide range of unique variants.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide epigenetic signatures facilitated the variant classification of the PURA gene and uncovered the pathomechanism of PURA-related neurodevelopmental disorders","authors":"Bing Xiao ,&nbsp;Weiqian Dai ,&nbsp;Yongkun Zhan ,&nbsp;Wenjuan Qiu ,&nbsp;Huiwen Zhang ,&nbsp;DanPing Liu ,&nbsp;Na Xu ,&nbsp;Yongguo Yu","doi":"10.1016/j.gim.2024.101167","DOIUrl":"10.1016/j.gim.2024.101167","url":null,"abstract":"<div><h3>Purpose</h3><p>Rare genetic variants in the <em>PURA</em> gene cause the <em>PURA</em>-related neurodevelopmental disorder (PURA-NDD), characterized by neonatal abnormalities and developmental delay. Using genome-wide DNA methylation analysis on patients with <em>PURA</em> variants, we aim to establish a PURA-NDD-specific methylation profile and provide further insights on the molecular basis of the PURA-NDD.</p></div><div><h3>Methods</h3><p>Twenty three individuals (including 12 unpublished) carrying <em>PURA</em> variants were enrolled. We conducted the Illumina Infinium EPIC microarray analysis in 17 PURA-NDD individuals. In vitro experiments were performed to examine how <em>PURA</em> variants affect Pur-a expression.</p></div><div><h3>Results</h3><p>Additional phenotypes in 12 newly identified patients were described in this study. Genome-wide DNA methylation analysis unveiled distinctive methylation profiles to PURA-NDD, and the established classifier can reclassify <em>PURA</em> variants of uncertain significance. Patients bearing <em>PURA</em> hapoloinsufficient and missense variants have comparable DNA methylation profiles, and cells expressing these <em>PURA</em> variants showed consistent Pur-a downregulation, suggesting a haploinsufficiency mechanism.</p></div><div><h3>Conclusion</h3><p>Patients with PURA-NDD exhibit a specific episignature, which has potential to aid identification and diagnosis of PURA-NDD patients and offer implications for further functional investigations.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141051472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder","authors":"","doi":"10.1016/j.gim.2024.101166","DOIUrl":"10.1016/j.gim.2024.101166","url":null,"abstract":"<div><h3>Purpose</h3><p>The function of <em>FAM177A1</em> and its relationship to human disease is largely unknown. Recent studies have demonstrated <em>FAM177A1</em> to be a critical immune-associated gene. One previous case study has linked <em>FAM177A1</em> to a neurodevelopmental disorder in 4 siblings.</p></div><div><h3>Methods</h3><p>We identified 5 individuals from 3 unrelated families with biallelic variants in <em>FAM177A1</em>. The physiological function of <em>FAM177A1</em> was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort.</p></div><div><h3>Results</h3><p>These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that <em>FAM177A1</em> localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA sequencing and metabolomic data sets from <em>FAM177A1</em>-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation.</p></div><div><h3>Conclusion</h3><p>Our data shed light on the emerging function of <em>FAM177A1</em> and defines <em>FAM177A1</em>-related neurodevelopmental disorder as a new clinical entity.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141044188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic and genetic spectra of galactose mutarotase deficiency: A nationwide survey conducted in Japan","authors":"Yasuko Mikami-Saito ,&nbsp;Yoichi Wada ,&nbsp;Natsuko Arai-Ichinoi ,&nbsp;Yoko Nakajima ,&nbsp;Sayaka Suzuki-Ajihara ,&nbsp;Kei Murayama ,&nbsp;Toju Tanaka ,&nbsp;Chikahiko Numakura ,&nbsp;Takashi Hamazaki ,&nbsp;Noboru Igarashi ,&nbsp;Hiroyuki Esaki ,&nbsp;Reiko Kagawa ,&nbsp;Tomotaka Kono ,&nbsp;Takaaki Sawada ,&nbsp;Tomo Sawada ,&nbsp;Hiromi Nyuzuki ,&nbsp;Hiroki Hirai ,&nbsp;Seiko Fumoto ,&nbsp;Junko Matsuda ,&nbsp;Ayako Matsunaga ,&nbsp;Shigeo Kure","doi":"10.1016/j.gim.2024.101165","DOIUrl":"10.1016/j.gim.2024.101165","url":null,"abstract":"<div><h3>Purpose</h3><p>Galactose mutarotase (GALM) deficiency was first reported in 2019 as the fourth type of galactosemia. This study aimed to investigate the clinical and genotypic spectra of GALM deficiency.</p></div><div><h3>Methods</h3><p>This was a questionnaire-based retrospective survey conducted in Japan between February 2022 and March 2023.</p></div><div><h3>Results</h3><p>We identified 40 patients with GALM deficiency in Japan (estimated prevalence: 1:181,835). Four of 38 patients (10.5%) developed cataracts, which resolved with lactose restriction in 3 out of 4 patients. Transient transaminitis was the most common symptom (23.1%). All of the patients followed lactose restriction; discontinuation of the restriction after infancy did not cause any complications. Moreover, none of the participants experienced long-term complications. Two variants, <em>GALM</em> NM_138801.3: c.294del and c.424G&gt;A, accounted for 72.5% of the identified pathogenic variants. The patients showed moderately elevated blood galactose levels with lactose intake; however, the elevation was lower than that observed in galactokinase deficiency.</p></div><div><h3>Conclusion</h3><p>GALM deficiency is characterized by a similar but milder phenotype and lower blood galactose elevation than in galactokinase deficiency. Diagnosis and initiation of lactose restriction in early infancy should be essential for prevention of cataracts, especially in cases of irreversible opacity.</p></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1098360024000996/pdfft?md5=2fa98fdd2daa9421884e08a14df2c32b&pid=1-s2.0-S1098360024000996-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}