Annals of Human Genetics最新文献

{"title":"Segregation analysis identifies specific alpha-defensin (DEFA1A3) SNP–CNV haplotypes in predisposition to IgA nephropathy","authors":"Nzar A. A. Shwan,&nbsp;Eric C. Moise,&nbsp;Paula E. Necsoiu,&nbsp;Amy J. Farr,&nbsp;Daniel P. Gale,&nbsp;Jonathan Barratt,&nbsp;John A. L. Armour","doi":"10.1111/ahg.12481","DOIUrl":"10.1111/ahg.12481","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immunoglobulin A (IgA) nephropathy is a disorder of the immune system affecting kidney function, and genome-wide association studies (GWAS) have defined numerous loci with associated variation, all implicating components of innate or adaptive immunity. Among these, single nucleotide polymorphisms (SNPs) in a region including the multiallelic copy number variation (CNV) of <i>DEFA1A3</i> are associated with IgA nephropathy in both European and Asian populations. At present, the precise factors underlying the observed associations at <i>DEFA1A3</i> have not been defined, although the key alleles differ between Asian and European populations, and multiple independent factors may be involved even within a single population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we measured <i>DEFA1A3</i> copy number in UK family trios with an offspring affected by IgA nephropathy, used the population distributions of joint SNP–CNV haplotypes to infer the likely segregation in trios, and applied transmission disequilibrium tests (TDT) to examine joint SNP–CNV haplotypes for over- or undertransmission into affected offspring from heterozygous parents.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results and Conclusions</h3>\u0000 \u0000 <p>We observed overtransmission of 3-copy class 2 haplotypes (raw <i>p</i> = 0.029) and some evidence for under-transmission of 3-copy class 1 haplotypes (raw <i>p</i> = 0.051), although these apparent effects were not statistically significant after correction for testing of multiple haplotypes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"87 1-2","pages":"1-8"},"PeriodicalIF":1.9,"publicationDate":"2022-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12481","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9422881","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":"Germline variants screening of MLH1, MSH2, MSH6 and PMS2 genes in 64 Algerian Lynch syndrome families: The first nationwide study","authors":"Asma-Lamia Boumehdi,&nbsp;Farid Cherbal,&nbsp;Feriel Khider,&nbsp;Mohammed Oukkal,&nbsp;Hassen Mahfouf,&nbsp;Ferhat Zebboudj,&nbsp;Mustapha Maaoui","doi":"10.1111/ahg.12482","DOIUrl":"10.1111/ahg.12482","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Colorectal cancer is the second leading cause of cancer-related deaths in women and men in Algeria. Lynch syndrome (LS) is an autosomal dominant disease caused by heterozygous germline pathogenic variants in mismatch repair genes (MMR) and frequently predisposes to colorectal cancer. However, data about MMR germline pathogenic variants in Algerian patients are limited. This first nationwide study aims to describe clinicopathologic features and germline variants in MMR genes in Algerian families with suspected LS. Sixty-four (64) families with suspected LS were studied. Index cases with LS who fulfilled Amsterdam criteria were screened by PCR-direct sequencing for germline variants in MMR genes: <i>MLH1</i> (exons 1, 9, 10, 13, 16), <i>MSH2</i> (exons 5, 6, 7, 12), <i>MSH6</i> (exons 4 and 8) and <i>PMS2</i> (exons 6 and 10). We selected these specific risk exons genes since they have a higher probability of harboring pathogenic variants. In addition, two unrelated LS patients were screened by next-generation sequencing using a cancer panel of 30 hereditary cancer genes. Six germline pathogenic variants and one germline likely pathogenic variant were identified in 19 (29.68%) families (4 <i>MLH1</i>, 2 <i>MSH2</i> and 1 <i>MSH6</i>). Of index cases and relatives who underwent genetic testing (<i>n</i> = 76), 30 (39.47%) had MMR pathogenic gene variants, one (0.13%) had MMR gene likely pathogenic variant and three had MMR variant of uncertain significance, respectively. Two novel germline pathogenic variants in <i>MLH1</i> (2) and one germline likely pathogenic variant in <i>MSH6</i> (1) never published in individuals with LS have been detected in the present study. The recurrent <i>MLH1</i> germline pathogenic variant c.1546C&gt;T has been found in nine LS families, six of them related with two large kindreds, from four North central provinces of Algeria. In addition, the common <i>MSH2</i> germline pathogenic variant c.942+3A&gt;T has been detected in five unrelated patients with a strong LS family history. The accumulative knowledge about clinicopathological and genetic characteristics of LS in Algerian patients will impact clinical management in the areas of both prevention and treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 6","pages":"328-352"},"PeriodicalIF":1.9,"publicationDate":"2022-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33449476","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":"Study of variants in genes implicated in rare familial migraine syndromes and their association with migraine in 200,000 exome-sequenced UK Biobank participants","authors":"Katherine Alexis Markel,&nbsp;David Curtis","doi":"10.1111/ahg.12484","DOIUrl":"10.1111/ahg.12484","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>A number of genes have been implicated in rare familial syndromes which have migraine as part of their phenotype but these genes have not previously been implicated in the common form of migraine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Among exome-sequenced participants in the UK Biobank, we identified 7194 migraine cases with the remaining 193,433 participants classified as controls. We investigated rare variants in 10 genes previously reported to be implicated in conditions with migraine as a prominent part of the phenotype and carried out gene- and variant-based tests for association.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found no evidence for association of these genes or variants with the common form of migraine seen in our subjects. In particular, a frameshift variant in <i>KCNK18</i>, p.(Phe139Trpfs*24), which had been shown to segregate with migraine with aura in a multiply affected pedigree, was found in 196 (0.10%) controls as well as in 10 (0.14%) cases (<i>χ</i>² = 0.96, 1 df, <i>p</i> = 0.33).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Since there is no other reported evidence to implicate <i>KCNK18</i>, we conclude that this gene and its product, TRESK, should no longer be regarded as being involved in migraine aetiology. Overall, we do not find that rare, functional variants in genes previously implicated to be involved in familial syndromes including migraine as part of the phenotype make a contribution to the commoner forms of migraine observed in this population.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 6","pages":"353-360"},"PeriodicalIF":1.9,"publicationDate":"2022-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12484","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9915015","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":"A splice site variant in TCTN3 underlies an atypical form of orofaciodigital syndrome IV","authors":"Shabir Hussain,&nbsp;Shoaib Nawaz,&nbsp;Hammal Khan,&nbsp;Anushree Acharya,&nbsp;Isabelle Schrauwen,&nbsp;Wasim Ahmad,&nbsp;Suzanne M. Leal","doi":"10.1111/ahg.12462","DOIUrl":"10.1111/ahg.12462","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Orofaciodigital syndrome (OFD) is clinically heterogeneous and is characterized by abnormalities in the oral cavity, facial features, digits, and central nervous system. At least 18 subtypes of the condition have been described in the literature. OFD is caused by variants in several genes with overlapping phenotypes. We studied a consanguineous Pakistani family with two affected siblings with an atypical form of OFD type 4 (OFD4). In addition to the typical features of OFD4 that include limb defects and growth retardation, the siblings displayed rare features of scaphocephaly and seizures. Exome sequencing analysis revealed a novel homozygous splice site variant c.257-1G&gt;A in <i>TCTN3</i> that segregated with disease. This homozygous splice site variant in <i>TCTN3</i> is most likely the underlying cause of the atypical form of OFD4 observed in this family. Our results contribute to the phenotypic spectrum of <i>TCTN3</i> associated ciliopathies and will facilitate better clinical diagnosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 6","pages":"291-296"},"PeriodicalIF":1.9,"publicationDate":"2022-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/13/24/AHG-86-291.PMC9804382.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10823074","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":"A novel splicing variant in GALNS in mucopolysaccharidosis IVA and the necessity of re-evaluating primer sequences","authors":"Sang-Mi Kim,&nbsp;Eu Seon Noh,&nbsp;Jong-Ho Park,&nbsp;Hyung-Doo Park,&nbsp;Soo-Youn Lee,&nbsp;Ja-Hyun Jang,&nbsp;Sung Yoon Cho","doi":"10.1111/ahg.12483","DOIUrl":"10.1111/ahg.12483","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Mucopolysaccharidosis type IVA (MPS IVA; Morquio syndrome type A) is an autosomal recessive disorder caused by defects in the lysosomal hydrolase N-acetylgalactosamine-6-sulfatase (<i>GALNS</i>) gene, leading to progressive systemic skeletal dysplasia. Early diagnosis and early intervention with enzyme replacement therapy are crucial for improving outcomes in these patients. However, a relatively high number of patients are genetically undiagnosed due to high allelic heterogeneity and the absence of robust functional evidence for most variants of the <i>GALNS</i> gene. Herein, we report a novel intronic variant identified with RNA analysis and an allele dropout (ADO) event caused by a common benign variant in the primer-binding site in a Korean boy with MPS IVA.</p>\u0000 \u0000 <p>A 28-month-old boy presented with pectus carinatum, kyphoscoliosis, and joint hypermobility with multiple skeletal dysplasia involving the vertebrae and hip joint. Total urinary glycosaminoglycans were elevated with a predominant keratan sulfate fraction, and GALNS (EC 3.1.6.4) activity was significantly decreased in leukocytes. Sanger sequencing was performed; however, only one heterozygous intronic variant with uncertain clinical significance, c.566+3A &gt; T (p.(?)), was identified. As the patient exhibited clinical and biochemical features of MPS IVA, we conducted whole genome sequencing (WGS) of the patient and his family to clarify the molecular diagnosis. WGS revealed a compound heterozygous genotype, c.1019G &gt; A (p.(Gly340Asp)) and c.566+3A &gt; T (p.(?)), in the <i>GALNS</i> gene. On mRNA sequencing, c.566+3A &gt; T, was confirmed to cause exon 5 skipping and a premature stop codon. With subsequent investigation, we discovered that the variant, c.1019G &gt; A, was undetected on initial sequencing because of ADO due to a common benign variant (rs3859024:G &gt; C) at the primer annealing location.</p>\u0000 \u0000 <p>We present a novel intronic variant with a splicing defect in the <i>GALNS</i> gene and suggest that clinicians review primer sequences in cases not diagnosed on Sanger sequencing before progressing to diagnostic steps such as WGS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 6","pages":"361-368"},"PeriodicalIF":1.9,"publicationDate":"2022-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40421604","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":"Applicability of the IrisPlex system for eye color prediction in an admixed population from Argentina","authors":"Diana María Hohl,&nbsp;Rebeca González,&nbsp;Gabriela Paula Di Santo Meztler,&nbsp;Jessica Patiño-Rico,&nbsp;Cristina Dejean,&nbsp;Sergio Avena,&nbsp;María De Los Ángeles Gutiérrez,&nbsp;Cecilia Inés Catanesi","doi":"10.1111/ahg.12480","DOIUrl":"10.1111/ahg.12480","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Eye color prediction based on an individual's genetic information is of interest in the field of forensic genetics. In recent years, researchers have studied different genes and markers associated with this externally visible characteristic and have developed methods for its prediction. The IrisPlex represents a validated tool for homogeneous populations, though its applicability in populations of mixed ancestry is limited, mainly regarding the prediction of intermediate eye colors. With the aim of validating the applicability of this system in an admixed population from Argentina (n = 302), we analyzed the six single nucleotide variants used in that multiplex for eye color and four additional SNPs, and evaluated its prediction ability. We also performed a genotype–phenotype association analysis. This system proved to be useful when dealing with the extreme ends of the eye color spectrum (blue and brown) but presented difficulties in determining the intermediate phenotypes (green), which were found in a large proportion of our population. We concluded that these genetic tools should be used with caution in admixed populations and that more studies are required in order to improve the prediction of intermediate phenotypes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 6","pages":"297-327"},"PeriodicalIF":1.9,"publicationDate":"2022-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40706536","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":"GR-α and GR-β mRNA levels in peripheral blood mononuclear cells of acute myelitis patients can assist in the identification of glucocorticoid sensitivity and are correlated with glucocorticoid therapeutic effect","authors":"Bolin Tang,&nbsp;Jun Han,&nbsp;Fen Wang,&nbsp;Xiang Li,&nbsp;Chaoyang Zhao","doi":"10.1111/ahg.12472","DOIUrl":"10.1111/ahg.12472","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Acute myelitis (AM) is a rare neuro-immune spinal cord disease. This study sought to explore the transcription level of glucocorticoid (GC) receptors α and β (GR-α/GR-β) in peripheral blood mononuclear cells (PBMCs) and their correlation with GC efficacy and sensitivity in AM patients. AM patients were grouped into the GC-sensitive group (<i>N</i> = 80) and GC-refractory group (<i>N</i> = 67). The GR-α and GR-β mRNA levels in PBMCs were detected. The differentiating value of GR-α, GR-β, and GR-α + GR-β on GC sensitivity and resistance in AM patients was assessed. The independent correlation between GR-α and GR-β mRNA levels and GC sensitivity in AM patients,t and the correlation between GR-α and GR-β mRNA levels and spinal function after GC treatment were analyzed. GR-α mRNA level in PBMCs of GC-refractory patients was lower than that of GC-sensitive patients, while GR-β mRNA level was higher than that of GC-sensitive patients. GR-α + GR-β mRNA had a high diagnostic value for GC sensitivity and resistance in AM patients (area under the ROC curve = 0.881, sensitivity = 79.1%, specificity = 85.0%). GR-α and GR-β mRNA levels were independently correlated with GC sensitivity. GR-α and GR-β mRNA levels were correlated with the spinal function of AM patients after GC treatment. Overall, GR-α and GR-β mRNA levels in PBMCs of AM patients can assist in the identification of GC sensitivity and are correlated with GC efficacy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 5","pages":"268-277"},"PeriodicalIF":1.9,"publicationDate":"2022-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40178381","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":"Using potential variable to study gene–gene and gene–environment interaction effects with genetic model uncertainty","authors":"Xiaonan Hu,&nbsp;Zhen Meng","doi":"10.1111/ahg.12470","DOIUrl":"10.1111/ahg.12470","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>One of the critical issues in genetic association studies is to evaluate the risk of a disease associated with gene–gene or gene–environment interactions. The commonly employed procedures are derived by assigning a particular set of scores to genotypes. However, the underlying genetic models of inheritance are rarely known in practice. Misspecifying a genetic model may result in power loss. By using some potential genetic variables to separate the genotype coding and genetic model parameter, we construct a model-embedded score test (MEST). Our test is free of assumption of gene–environment independence and allows for covariates in the model. An effective sequential optimization algorithm is developed. Extensive simulations show the proposed MEST is robust and powerful in most of scenarios. Finally, we apply the proposed method to rheumatoid arthritis data from the Genetic Analysis Workshop 16 to further investigate the potential interaction effects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 5","pages":"257-267"},"PeriodicalIF":1.9,"publicationDate":"2022-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"62795854","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":"DRD4 polymorphism associated with greater positive affect in response to negative and neutral social stimuli","authors":"T. Lee Gilman,&nbsp;Matthew T. Ford,&nbsp;Aaron M. Jasnow,&nbsp;Karin G. Coifman","doi":"10.1111/ahg.12471","DOIUrl":"10.1111/ahg.12471","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Despite the robustness of <i>DRD4</i> polymorphism associations with brain-based behavioral characteristics in candidate gene research, investigations have minimally explored associations between these polymorphisms and emotional responses. In particular, the prevalent single nucleotide polymorphism (SNP) -521C/T (rs1800955) in the promoter region of <i>DRD4</i> remains unexplored relative to emotions. Here, two independent samples were evaluated using different emotion elicitation tasks involving social stimuli: Study 1 (<i>N</i> = 120) evoked positive and negative emotional responses to validated film clips; Study 2 (<i>N</i> = 122) utilized Cyberball to simulate social rejection and acceptance. Across studies, C/C individuals self-reported higher mean positive affect scores using Likert scales versus T carrier individuals, selectively when presented with neutral or negative (but not positive) social stimuli. The consistent findings across these two studies supports a functional consequence of this <i>DRD4</i> SNP on emotion processing during changing social contexts. Continued investigation will help clarify if a C/C genotype enhances positive emotions under negative circumstances, or if the presence of the T allele reduces positive emotions, and how rs1800955 behavioral associations might generalize across different demographics. Future studies could also reveal if this SNP interacts with other changing environmental conditions to affect emotional responses, such as social limitations during the COVID-19 pandemic.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 4","pages":"218-223"},"PeriodicalIF":1.9,"publicationDate":"2022-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12471","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48881349","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":"A novel leaky splice variant in centromere protein J (CENPJ)-associated Seckel syndrome","authors":"Navneesh Yadav,&nbsp;Laxmi Kirola,&nbsp;Thenral S Geetha,&nbsp;Kirti Mittal,&nbsp;Jayarama Kadandale,&nbsp;Yuval Yogev,&nbsp;Ohad S. Birk,&nbsp;Neerja Gupta,&nbsp;Prahlad Balakrishnan,&nbsp;Manisha Jana,&nbsp;Meena Gupta,&nbsp;Madhulika Kabra,&nbsp;Bittianda Kuttapa Thelma","doi":"10.1111/ahg.12469","DOIUrl":"10.1111/ahg.12469","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Primary microcephaly and Seckel syndrome are rare genetically and clinically heterogenous brain development disorders. Several exonic/splicing mutations are reported for these disorders to date, but ∼40% of all cases remain unexplained. We aimed to uncover the genetic correlate(s) in a family of multiple siblings with microcephaly. A novel homozygous intronic variant (NC_000013.10:g.25459823T&gt;C) in <i>CENPJ</i> (13q12) segregating with all four affected male siblings was identified by exome sequencing and validated by targeted linkage approach (logarithm of the odds score 1.8 at θ 0.0). RT-PCR of <i>CENPJ</i> in affected siblings using their EBV derived cell lines showed aberrant transcripts suggestive of exon skipping confirmed by Sanger sequencing. Significantly reduced wild type transcript/protein in the affected siblings having the splice variant indicates a leaky gene expression of pathological relevance. Based on known <i>CENPJ</i> function, assessing for mitotic alterations revealed defect in centrosome duplication causing mono/multicentrosome(s) at prophase, delayed metaphase, and unequal chromosomal segregation in patient cells. Clinical features witnessed in this study expand the spectrum of <i>CENPJ</i>-associated primary microcephaly and Seckel syndrome. Furthermore, besides the importance of regulatory variants in classical monogenic disorders these findings provide new insights into splice site biology with possible implications for ASO-based therapies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"86 5","pages":"245-256"},"PeriodicalIF":1.9,"publicationDate":"2022-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47623842","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}