Annals of Human Genetics最新文献

{"title":"Pitfalls of predicting age-related traits by polygenic risk scores","authors":"Valentina Escott-Price,&nbsp;Karl Michael Schmidt","doi":"10.1111/ahg.12520","DOIUrl":"10.1111/ahg.12520","url":null,"abstract":"<p>Polygenic risk scores (PRS) are a method increasingly used to capture the combined effect of genome-wide significant variants and those which individually do not show genome-wide significant association but are likely to contribute to the risk of developing diseases. However, their practical use incurs complications and inconsistencies that so far limit their clinical applicability. The aims of the present review are to discuss the PRS for age-related diseases and to highlight pitfalls and limitations of PRS prediction accuracy due to ageing and mortality effects. We argue that the PRS is widely used but the individual's PRS values differ substantially depending on the number of genetic variants included, the discovery GWAS and the method employed to generate them. Moreover, for neurodegenerative disorders, although an individual's genetics do not change with age, the actual score depends on the age of the sample used in the discovery GWAS and is likely to reflect the individual's disease risk at this particular age. Improvement of PRS prediction accuracy for neurodegenerative disorders will come from two sides, both the precision of clinical diagnoses, and a careful attention to the age distribution in the underlying samples and validation of the prediction in longitudinal studies.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 5","pages":"203-209"},"PeriodicalIF":1.9,"publicationDate":"2023-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12520","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10053150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic polymorphism and variability in the Guangdong Hakka, Teochew, and Cantonese groups: A comprehensive analysis of 19 X-STRs","authors":"Cheng Xiao,&nbsp;Xingyi Yang,&nbsp;Zhonghao Yu,&nbsp;Weibin Wu,&nbsp;Yuan Wang,&nbsp;Quyi Xu,&nbsp;Ling Chen","doi":"10.1111/ahg.12518","DOIUrl":"10.1111/ahg.12518","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>X chromosomeshort tandem repeat (X-STR) loci are playing an increasingly important role inforensic work, identifying female traces in male contamination and explainingcomplex kinship analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we analyzed thegenetic polymorphism of 19 X-STR loci in the Guangdong Hakka, Teochew and Cantonese groups, respectively, aswell as in the Guangdong Hakka, Teochew andCantonese pooled Han. The genetic diversity and forensic characteristics of the19 X-STRs and 7 linkage groups were investigated, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The experiments showed that the genetic diversity (GD) and polymorphism information content (PIC) in the pooledGuangdong Han ranged from 0.5320 to 0.9234 and 0.4369 to 0.9171, respectively, and the cumulative power of discrimination for males (PDM), power of discrimination for females (PDF) and mean paternity exclusion chance (MEC) were higher than 0.9999999, indicating that the 19 X-STRs had high geneticpolymorphism and discriminatory power. Genetic differences among Chinese Hansubgroups and among different Chinese populations were investigated byphylogenetic reconstruction and principal component analysis (PCA), respectively. Genetic analyses based on neighbor-joining (NJ) tree and principal component analysis plot showed that Cantonese, Teochew and Hakka were closely genetically related, and different populations with closer linguistic components had more genetic affinity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study adds to the forensic X-STR database and demonstrates the forensic efficiency of 19 X-STRs for the Hakka, Teochewand Cantonese populations in Guangdong, and the pooled Han of Hakka, Teochewand Cantonese people in Guangdong.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 5","pages":"232-240"},"PeriodicalIF":1.9,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10112288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-pass whole genome sequencing is a reliable and cost-effective approach for copy number variant analysis in the clinical setting","authors":"P. Mazzonetto, Darine Villela, S. S. da Costa, A. Krepischi, F. Milanezi, M. Migliavacca, P. Pierry, A. Bonaldi, Luiz Gustavo D Almeida, Camila Alves De Souza, J. E. Kroll, Marcelo G. Paula, R. Guarischi-Sousa, C. Scapulatempo-Neto, C. Rosenberg","doi":"10.1101/2023.05.26.23290606","DOIUrl":"https://doi.org/10.1101/2023.05.26.23290606","url":null,"abstract":"We evaluated the performance of low-pass whole genome sequencing (LP-WGS) to detect copy number variants (CNVs) in clinical cytogenetics. DNA samples with known CNVs detected by chromosomal microarray analyses (CMA) were selected for comparison; our panel included 44 DNA samples (12 prenatal and 32 postnatal), comprising a total of 55 chromosome imbalances. The selected cases were chosen to provide a wide range of clinically relevant CNVs, being the vast majority associated with intellectual disability or recognizable syndromes. The chromosome imbalances ranged in size from 75 kb to 90.3 Mb, including aneuploidies and two cases of mosaicism. All CNVs were successfully detected by LP-WGS, showing a high level of consistency and robust performance of the sequencing method. Notably, the size of chromosome imbalances detected by CMA and LP-WGS were compatible between the two different platforms, which indicates that the resolution and sensitivity of the LP-WGS approach are at least similar to those provided by CMA. Our data show the potential use of LP-WGS to detect CNVs in clinical diagnosis and confirm the method as an alternative for chromosome imbalances detection. The diagnostic effectiveness and feasibility of LP-WGS, in this technical validation study, were evidenced by a clinically representative dataset of CNVs that allowed a systematic assessment of the detection power and the accuracy of the sequencing approach. Further, since the software used in this study is commercially available, the method can be easily tested and implemented in a routine diagnostic setting.","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"1 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47211406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of influential rare variants in aggregate testing using random forest importance measures","authors":"Rachel Z. Blumhagen,&nbsp;David A. Schwartz,&nbsp;Carl D. Langefeld,&nbsp;Tasha E. Fingerlin","doi":"10.1111/ahg.12509","DOIUrl":"10.1111/ahg.12509","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Aggregate tests of rare variants are often employed to identify associated regions compared to sequentially testing each individual variant. When an aggregate test is significant, it is of interest to identify which rare variants are “driving” the association. We recently developed the rare variant influential filtering tool (RIFT) to identify influential rare variants and showed RIFT had higher true positive rates compared to other published methods. Here we use importance measures from the standard random forest (RF) and variable importance weighted RF (vi-RF) to identify influential variants. For very rare variants (minor allele frequency [MAF] &lt; 0.001), the vi-RF:Accuracy method had the highest median true positive rate (TPR = 0.24; interquartile range [IQR]: 0.13, 0.42) followed by the RF:Accuracy method (TPR = 0.16; IQR: 0.07, 0.33) and both were superior to RIFT (TPR = 0.05; IQR: 0.02, 0.15). Among uncommon variants (0.001 &lt; MAF &lt; 0.03), the RF methods had higher true positive rates than RIFT while observing comparable false positive rates. Finally, we applied the RF methods to a targeted resequencing study in idiopathic pulmonary fibrosis (IPF), in which the vi-RF approach identified eight and seven variants in <i>TERT</i> and <i>FAM13A</i>, respectively. In summary, the vi-RF provides an improved, objective approach to identifying influential variants following a significant aggregate test. We have expanded our previously developed R package RIFT to include the random forest methods.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 4","pages":"184-195"},"PeriodicalIF":1.9,"publicationDate":"2023-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12509","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9679285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of common BRCA1 variants with predisposition to breast tumors in Pakistan","authors":"Ayesha Siddique,&nbsp;Warda Fatima,&nbsp;Naeem Shahid","doi":"10.1111/ahg.12511","DOIUrl":"10.1111/ahg.12511","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p><i>BRCA1</i> variants are extensively associated with increased risk of breast cancer. Early detection and screening of variants is still rare in developing countries. Here, we investigated six <i>BRCA1</i> variants in 300 subjects from Pakistani population using tetra amplification-refractory mutation system (T-ARMS) PCR. Our results indicate significant association of <i>BRCA1</i> variants rs8176237 (AA; OR 8.2, 95% CI 3.02–22.64, <i>p</i> &lt; 0.0001), rs1060915 (CC; OR 4.29, 95% CI 1.94–9.48, <i>p</i> = 0.0003), and rs799912 (TT; OR 3.16, 95% CI 1.44–6.94, <i>p</i> = 0.004) with up to 8-fold increased odds of breast cancer under recessive model. Furthermore, <i>BRCA1</i> haplotypes AGCACG and AGCCCT were associated with up to 18% breast cancer cases (<i>p</i> &lt; 0.05). Additionally, we found association of these variants with up to 11-fold increased odds of benign breast tumors. Linkage disequilibrium (LD) block-wise analysis revealed haplotypes GCAC and ATAC were associated with significantly increased risk. To our knowledge, this is the first study that identifies the association of these <i>BRCA1</i> variants with breast tumors in Pakistani population. In conclusion, <i>BRCA1</i> variants investigated in the present study are associated with high odds of benign- and malignant breast tumors. Studies with bigger sample size may help early detection and screening to reduce the odds of breast cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 5","pages":"222-231"},"PeriodicalIF":1.9,"publicationDate":"2023-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12511","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10054619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic portrait of the Amazonian communities of Peru and Bolivia: The legacy of the Takanan-speaking people","authors":"José R. Sandoval,&nbsp;Susana Revollo,&nbsp;Cinthia Cuellar,&nbsp;Daniela R. Lacerda,&nbsp;Marilza S. Jota,&nbsp;Ricardo Fujita,&nbsp;Fabricio R. Santos","doi":"10.1111/ahg.12510","DOIUrl":"10.1111/ahg.12510","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>During the colonial period in South America, many autochthonous populations were affected by relocation by European missionary reductions and other factors that impacted and reconfigured their genetic makeup. Presently, the descendants of some “reduced” and other isolated groups are distributed in the Amazonian areas of Peru, Bolivia, and Brazil, and among them, speakers of Takanan and Panoan languages. Based on linguistics, these peoples should be closely related, but so far no DNA comparison studies have been conducted to corroborate a genetic relationship. To clarify these questions, we used a set of 15 short tandem repeats of the non-recombining part of the Y-chromosome (Y-STRs) and mitochondrial DNA (mtDNA) control region sequence data. Paternal line comparisons showed the Takanan-speaking peoples from Peru and Bolivia descended from recent common ancestors; one group was related to Arawakan, Jivaroan, and Cocama and the other to Panoan speakers, consistent with linguistics. Also, a genetic affinity for maternal lines was observed between some Takanan speakers and individuals who spoke different Amazonian languages. Our results supported a shared ancestry of Takanan, Panoan, Cocama, and Jivaroan-speaking communities who appeared to be related to each other and came likely from an early Arawak expansion in the western Amazonia of South America.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 5","pages":"210-221"},"PeriodicalIF":1.9,"publicationDate":"2023-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12510","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10111752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular genetic diagnosis of kidney ciliopathies: Lessons from interpreting genomic sequencing data and the requirement for accurate phenotypic data","authors":"Sarah Orr,&nbsp;Eric Olinger,&nbsp;Sotia Iosifidou,&nbsp;Miguel Barroso-Gil,&nbsp;Ruxandra Neatu,&nbsp;Katrina Wood,&nbsp;Ian Wilson,&nbsp;Genomics England Research Consortium,&nbsp;John Andrew Sayer","doi":"10.1111/ahg.12508","DOIUrl":"10.1111/ahg.12508","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p><b>Introduction</b>: Massively parallel sequencing (MPS) techniques have made a major impact on the identification of the genetic basis of inherited kidney diseases such as the ciliopathy autosomal dominant polycystic kidney disease (ADPKD). Great care must be taken when analysing MPS data in isolation from accurate phenotypic information, as this can cause misdiagnosis. <b>Methods</b>: Here, we describe a family trio, recruited to the Genomics England 100,000 Genomes Project, labelled as having cystic kidney disease, who were genetically unsolved following routine data analysis pipelines. We performed a bespoke reanalysis of Whole Genome Sequencing (WGS) data and coupled this with revised phenotypic data and targeted PCR and Sanger sequencing to provide a precise molecular genetic diagnosis. <b>Results</b>: We detected a heterozygous <i>PKD1</i> frameshift variant within the WGS data which segregated with the redefined ADPKD phenotypes. An additional heterozygous exon deletion in <i>ALG8</i> was also found in affected and unaffected individuals, but its precise clinical significance remains unclear. <b>Conclusion</b>: This case illustrates that reanalysis of WGS data in unsolved cases of cystic kidney disease is valuable. Clinical phenotypes must be reassessed as these may have been incorrectly recorded and evolve over time. Undertaking additional studies including genotype-phenotype correlation in wider family members provides useful diagnostic information.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"88 1","pages":"76-85"},"PeriodicalIF":1.9,"publicationDate":"2023-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9284677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of obesity on lung function measurements and respiratory disease: A Mendelian randomization study","authors":"Jiayan Liu,&nbsp;Hanfei Xu,&nbsp;L Adrienne Cupples,&nbsp;George T. O’ Connor,&nbsp;Ching-Ti Liu","doi":"10.1111/ahg.12506","DOIUrl":"10.1111/ahg.12506","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Observational studies have shown that body mass index (BMI) and waist-to-hip ratio (WHR) are both inversely associated with lung function, as assessed by forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). However, observational data are susceptible to confounding and reverse causation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We selected genetic instruments based on their relevant large-scale genome-wide association studies. Summary statistics of lung function and asthma came from the UK Biobank and SpiroMeta Consortium meta-analysis (<i>n</i> = 400,102). After examining pleiotropy and removing outliers, we applied inverse-variance weighting to estimate the causal association of BMI and BMI-adjusted WHR (WHRadjBMI) with FVC, FEV1, FEV1/FVC, and asthma. Sensitivity analyses were performed using weighted median, MR-Egger, and MRlap methods.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that BMI was inversely associated with FVC (effect estimate, −0.167; 95% confidence interval (CI), −0.203 to −0.130) and FEV1 (effect estimate, −0.111; 95%CI, −0.149 to −0.074). Higher BMI was associated with higher FEV1/FVC (effect estimate, 0.079; 95%CI, 0.049 to 0.110) but was not significantly associated with asthma. WHRadjBMI was inversely associated with FVC (effect estimate, −0.132; 95%CI, −0.180 to −0.084) but has no significant association with FEV1. Higher WHR was associated with higher FEV1/FVC (effect estimate, 0.181; 95%CI, 0.130 to 0.232) and with increased risk of asthma (effect estimate, 0.027; 95%CI, 0.001 to 0.053).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We found significant evidence that increased BMI is suggested to be causally related to decreased FVC and FEV1, and increased BMI-adjusted WHR could lead to lower FVC value and higher risk of asthma. Higher BMI and BMI-adjusted WHR were suggested to be causally associated with higher FEV1/FVC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 4","pages":"174-183"},"PeriodicalIF":1.9,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12506","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9759606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of pathogenic deep intronic variant and exonic LINE-1 insertion in a patient with Meckel syndrome","authors":"Sachiko Miyamoto,&nbsp;Kazuyuki Nakamura,&nbsp;Mitsuhiro Kato,&nbsp;Mitsuko Nakashima,&nbsp;Hirotomo Saitsu","doi":"10.1111/ahg.12507","DOIUrl":"10.1111/ahg.12507","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Biallelic <i>CC2D2A</i> variants are associated with a wide range of neurodevelopmental disorders including Meckel syndrome. Here we report a Japanese girl with Meckel syndrome harboring a pathogenic deep intronic variant (NM_001378615.1:c.1149+3569A&gt;G) and an exonic LINE-1 insertion, which was predicted to cause aberrant splicing by SpliceAI and was detected by TEMP2 program, respectively. RNA analysis using urine-derived cells (UDCs) showed retention of 149-bp intronic sequences, leading to frameshift. Immunoblotting showed marked reduction of CC2D2A protein in the patient. Our report demonstrated that utilization of transposon detection tool and functional analysis using UDCs will increase diagnostic yield of genome sequencing.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 4","pages":"196-202"},"PeriodicalIF":1.9,"publicationDate":"2023-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10048542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three siblings with variable degrees of neuromuscular involvement and congenital sideroblastic anemia: A peculiar phenotype and a surprise genotypic explanation","authors":"Mai Abd El Salam,&nbsp;Khaled Salama,&nbsp;Yasmeen M. M. Selim,&nbsp;Mariam Saad,&nbsp;Rasha Rady,&nbsp;Salem Alawbathani,&nbsp;Sabine Schroeder,&nbsp;Mohamed A. Elmonem,&nbsp;Nour Elkhateeb","doi":"10.1111/ahg.12505","DOIUrl":"10.1111/ahg.12505","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <p>Introduction: Congenital sideroblastic anemias (CSAs) are a group of inherited bone-marrow disorders manifesting with erythroid hyperplasia and ineffective erythropoiesis. Methods: We describe a detailed clinical and genetic characterization of three siblings with CSA. Results: Two of them had limb-girdle myopathy and global developmental delay. The two elder siblings performed allogenic hematopoietic stem-cell transplantation 5 and 3 years prior with stabilization of the hematological features. Exome sequencing in the non-transplanted sibling revealed a novel homozygous nonsense variant in <i>SLC25A38</i> gene NM_017875.2:c.559C &gt; T; p.(Arg187*) causing autosomal-recessive sideroblastic anemia type-2, and a second homozygous pathogenic previously reported variant in <i>GMPPB</i> gene NM_013334.3:c.458C &gt; T; p.(Thr153Ile) causing autosomal-recessive muscular dystrophy-dystroglycanopathy type B14. With the established diagnosis, hematopoietic stem cell transplantation is now being scheduled for the youngest sibling, and a trial therapy with acetylcholine esterase inhibitors was started for the two neurologically affected patients with partial clinical improvement. Conclusion: This family emphasizes the importance of whole-exome sequencing for familial cases with complex phenotypes and vague neurological manifestations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 4","pages":"166-173"},"PeriodicalIF":1.9,"publicationDate":"2023-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9675243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}