Annals of Human Genetics最新文献

{"title":"Opportunities and Challenges of Population Pharmacogenomics.","authors":"Yitian Zhou, Yoomi Park, Mahamadou D Camara, Volker M Lauschke","doi":"10.1111/ahg.12596","DOIUrl":"https://doi.org/10.1111/ahg.12596","url":null,"abstract":"<p><p>Pharmacological responses can vary significantly among patients from different ethnogeographic backgrounds. This variability can, at least in part, be attributed to population-specific genetic patterns in genes involved in drug absorption, distribution, metabolism, and excretion, as well as in genes associated with drug-induced toxicity. Identification of such ethnogeographic variability is thus crucial for the optimization of precise population-specific drug treatments. In this review, we summarize the current knowledge about the clinically actionable pharmacogenetic diversity of genes involved in drug metabolism (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, TPMT, NUDT15, UGT1A1, and NAT2), drug-induced hypersensitivity reactions (HLA-A and HLA-B), and drug-induced acute hemolytic anemia (G6PD). We highlight risk populations with distinct allele frequencies and discuss implications for the customization of treatment. Subsequently, we discuss key challenges and opportunities in population pharmacogenomics, including the importance of considering distinct allele frequency patterns in indigenous or founder populations, interpreting pharmacogenomic response in admixed populations, addressing the investigation bias of the pharmacogenomic literature, and difficulties in including rare and population-specific variants into drug response predictions. The information provided here underscores the critical role of population pharmacogenomics in refining pharmacological treatment strategies and aspires to provide further guidance to maximize the benefits of precision medicine across populations.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12596"},"PeriodicalIF":1.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762615","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":"Genetic Determinants of the Familial Hypercholesterolaemia Phenotype.","authors":"Steve Eric Humphries, Marta Futema","doi":"10.1111/ahg.12594","DOIUrl":"https://doi.org/10.1111/ahg.12594","url":null,"abstract":"<p><p>Individuals with familial hypercholesterolaemia (FH) have severely elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C) from birth and as a consequence have an elevated morbidity and mortality due to the development of coronary heart disease (CHD). Monogenic FH can be caused by carrying a single copy of a pathogenic variant in any of four genes (LDLR/APOB/PCSK9/APOE), which are all involved in the clearance of LDL-C from the blood by the liver. FH is one of the most common inherited disorders, with an estimated prevalence of carriers of around 1/280 individuals in most populations and ancestry groups. However, such variants can be found usually only in 20%-30% of clinically FH subjects, and in the majority of the no-variant individuals, the phenotype is most likely explained by the inheritance of a greater-than-average number of common variants of small effect, with such individuals better given the diagnosis of 'polygenic hypercholesterolaemia'. Also, in a proportion of no-variant subjects who meet the clinical criteria, the most likely explanation is due to overproduction of Lp(a) which is an LDL-C particle with a bound copy of the 'little-a' protein. Here, we review the research that has elucidated the genetic architecture of the FH phenotype and discuss recent studies and future prospects of finding additional genes where variants can cause FH.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12594"},"PeriodicalIF":1.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762593","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":"Novel CTSA Variant Identified in a Thai Family With Late-Infantile Galactosialidosis","authors":"Lukana Ngiwsara,&nbsp;Dhachdanai Dhachpramuk,&nbsp;Phannee Sawangareetrakul,&nbsp;Sherry Vongphit,&nbsp;Punchama Pacharn,&nbsp;Jisnuson Svasti,&nbsp;Nithiwat Vatanavicharn","doi":"10.1111/ahg.12595","DOIUrl":"10.1111/ahg.12595","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> ABSTRACT</h3>\u0000 \u0000 <p>Galactosialidosis (GS) is a rare lysosomal storage disease (LSD) with variable onset caused by a defect in protective protein/cathepsin A (PPCA) encoded by the <i>CTSA</i> gene. The late-infantile onset is characterized by developmental delay, visceromegaly, coarse facies, and cherry-red macula. We report cases of late-infantile GS in a Thai-Lahu family, with affected members initially presenting with recurrent infections due to T-cell defects. The clinical features of LSD and cherry-red macula led us to perform lysosomal enzyme assays, which showed undetectable activity of PPCA. A novel homozygous missense <i>CTSA</i> variant (NM_000308.4): c.1307<i>A </i>&gt; <i>G</i> (p.Gln436Arg) was identified in affected individuals. In vitro functional analysis suggested that the variant may impair the dimerization process of PPCA, potentially disrupting proper protein maturation or function and leading to significantly reduced PPCA activity. Exome sequencing did not reveal any variants in other genes associated with primary immunodeficiencies. To date, our cases represent the first reported patients with GS and T-cell defects. Our study broadened the clinical and genotype spectrum of this rare disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 2-3","pages":"126-131"},"PeriodicalIF":1.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12595","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750836","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":"Clinical Exome Sequencing Identifies, Two Homozygous LOXHD1 Variants in Two Inbred Families With Pre-Lingual Hearing Loss From South India","authors":"Mathuravalli Krishnamoorthy,&nbsp;Chandru Jayasankaran,&nbsp;Sorna Lakshmi,&nbsp;Chodisetty Sarvani,&nbsp;Jeffrey Justin Margret,&nbsp;Subathra Mahalingam,&nbsp;Pavithra Amritkumar,&nbsp;Paridhy Vanniya Subramanyam,&nbsp;Sarrath Rathnaraajan S,&nbsp;C. R. Srikumari Srisailapathy","doi":"10.1111/ahg.12593","DOIUrl":"10.1111/ahg.12593","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>In recent years, numerous genetic variants have been linked with prelingual hearing loss (HL). Variants in the <i>LOXHD1</i> gene (lipoxygenase homology domain—1) associated with <i>DFNB</i>77 are highly heterogeneous, with different auditory characteristics varying from stable to progressive and mild to profound. To date, 168 <i>DFNB</i>77 cases have been recorded worldwide. Forty-one hearing-impaired (HI) probands, who were previously excluded for a set of four common deafness-causing genes (viz.<i>, GJB2, GJB6, SLC26A4</i>, and <i>CDH23)</i> from 33 HI families, were subjected to clinical exome sequencing (CES) involving 285 genes associated with HL. This was followed by a segregation analysis of the available members in the family. We identified two pathogenic <i>LOXHD1</i> variants in two unrelated inbred families. One is a novel homozygous pathogenic nonsense variant (c.3999C &gt; A; p.C1333X), whereas the other is a likely pathogenic missense variant (c.6046G &gt; T; p.E2046K). In silico tools such as SIFT, PolyPhen-2, Mutation Taster, CADD, and REVEL scores were used to predict variant pathogenicity. Furthermore, American College of Medical Genetics and Genomics guidelines specific to HL were applied to finally classify a variant as pathogenic or otherwise. The frequency of <i>LOXHD1 variants</i> identified in our study is 4.88% (2/41). This is the first <i>LOXHD1</i> report associated with non-syndromic HL in South Indian families.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 2-3","pages":"114-125"},"PeriodicalIF":1.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603632","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":"Exploring and Expanding Secondary Findings Through Exome Sequencing in the Turkish Population","authors":"Mehmet Berkay Akcan,&nbsp;Canan Ceylan Köse,&nbsp;Kübra Müge Çelik,&nbsp;Koray Tekin,&nbsp;Derya Kaya,&nbsp;Fatma Sılan","doi":"10.1111/ahg.12592","DOIUrl":"10.1111/ahg.12592","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Exome-sequencing (ES) methods enable accurate diagnosis in challenging cases and uncover secondary findings (SFs) potentially linked to life-threatening or preventable diseases. The American College of Medical Genetics and Genomics (ACMG) publishes a list detailing which SFs should be reported and regularly updates it. We aimed to compare results across different SF versions in patients and explore additional SFs to identify potential new recommendations for SF reporting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a retrospective analysis of 724 patients to identify ACMG SFs using the QIAGEN Clinical Insight (QCI) Interpret database. Furthermore, we investigated pathogenic/likely pathogenic variants in cancer and cardiovascular disease genes not listed in ACMG SFs, as well as genes associated with common diseases prevalent in our country.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>ACMG SF v3.2 variants were identified in 56 patients (7.7%), with no observed differences between ACMG v3.1 and v3.2. Additionally, our analysis revealed that 208 patients harbored non-ACMG SF variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In this study, we focused on known SFs and identified additional variants that could be considered as new recommendations. While expanding the list of SFs can pose challenges during analyses and genetic counseling, a thoughtfully curated SF list has the potential to enhance patient care and improve clinical outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 2-3","pages":"106-113"},"PeriodicalIF":1.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498075","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":"RETRACTION: Investigating the Effectiveness of Forensic Genetics and Population Genetic Diversity Using a Multi-InDel System in Chinese Hezhou and Southern Shaanxi Han Populations","authors":"","doi":"10.1111/ahg.12590","DOIUrl":"10.1111/ahg.12590","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <p><b>RETRACTION</b>: Wang, X., Q. Lan, Y. Lin, et al. “Investigating the Effectiveness of Forensic Genetics and Population Genetic Diversity Using a Multi-InDel System in Chinese Hezhou and Southern Shaanxi Han Populations,” <i>Annals of Human Genetics</i> (Early View): https://doi.org/10.1111/ahg.12553.</p>\u0000 \u0000 <p>The above article, published online on 20 May 2024, in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by an agreement between the authors; the journal's Editor in Chief, Dr. Rosemary Ekong; University College London; and John Wiley &amp; Sons, Ltd.  The authors reported that a number of errors had been included in the published article, which would require corrections to the abstract, results, and conclusions, as well as Figure 5. The editors confirmed these errors. The retraction has been agreed to because the corrections required to amend these major errors would require substantial changes to the results and conclusions in the article. The authors have agreed to submit the revised version of this article for evaluation by the journal.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 2-3","pages":"132"},"PeriodicalIF":1.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12590","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998870","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":"Persistence of Ancestral KhoeSan Mitochondrial Patterns in Contemporary South African Populations.","authors":"Maria Eugenia D'Amato, Peter Ristow, Michelle Livesey, Kirsty Heynes, Nicole Huber, Claudio Bravi, Anders J Hansen, Walther Parson","doi":"10.1111/ahg.12589","DOIUrl":"https://doi.org/10.1111/ahg.12589","url":null,"abstract":"<p><strong>Introduction: </strong>Southern Africa has been inhabited by hunter-gatherers for at least 20,000 years and has received diverse immigration flows in the last 2000 years. The original inhabitants have interacted with the pastoralist migrants from Eastern Africa (∼2000 ybp), followed by the southern Bantu migration arriving some 1000 ybp, and more recently with the European and Asian settlers after the 17th century. Many of the original Khoekhoe and San inhabitants have either become extinct or have disappeared through admixture in South Africa (SA), in a sex-biased manner involving KhoeSan women.</p><p><strong>Methods: </strong>In this study, we generated mitochondrial DNA (mtDNA) control region (CR) sequences for 247 South African individuals. The sampling effort was concentrated in regions and populations with historical links to the KhoeSan population groups: admixed (Coloured, Griqua), Nama (Khoekhoe) and Bantu in three provinces. Here we evaluate the composition and extent of connectivity between population groups and regions, and to assess the distribution of haplotypes for the practical application of mtDNA CR data in forensic identifications.</p><p><strong>Results: </strong>The analysis of the newly generated sequences revealed 142 distinct haplotypes, of which 122 were unique. Haplogroup L0 was predominant (overall 71.7%). A high-frequency L0d2a haplotype dominated the pool of the admixed groups with 10%-12.5% incidence overall or per region. Comparative analysis with 545 extant mtDNA CR sequences from South African KhoeSan and admixed descendants revealed extensive population structure and high within-group haplotype sharing.</p><p><strong>Conclusion: </strong>The observed population and regional variations, combined with the prevalence of high-frequency haplotypes, align with patterns of matrilocality. These findings highlight the limitations of using mtDNA control region analysis for forensic applications in South Africa.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12589"},"PeriodicalIF":1.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943316","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":"Genotype and Haplotype Analysis With In Silico Prediction of TMPRSS2 Gene in Jordanian Population","authors":"Razan Issam Abu-Almfalfal,&nbsp;Yazun Bashir Jarrar,&nbsp;Munir Gharaibeh","doi":"10.1111/ahg.12588","DOIUrl":"10.1111/ahg.12588","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health concern. The entry of the virus into host cells is facilitated by the transmembrane protease serine 2 (TMPRSS2) receptor, and genetic variations in the <i>TMPRSS2</i> gene may influence disease susceptibility. However, there is a lack of knowledge regarding <i>TMPRSS2</i> genetic variants and haplotypes in the Jordanian population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This study aimed to characterize the genotype and haplotype variations in the <i>TMPRSS2</i> binding domain with SARS-CoV-2 among Jordanian volunteers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The binding domain of <i>TMPRSS2</i> with SARS-CoV-2 (Exons 9 and 10) was amplified using polymerase chain reaction (PCR) for a random sample of 120 healthy unrelated Jordanian volunteers, followed by Sanger DNA sequencing for the PCR products. The effect of the novel genetic variants on the TMPRSS2 protein structure was predicted using in silico methods.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results showed significant (<i>p</i> &lt; 0.05, chi-square) allele frequencies for known <i>TMPRSS2</i> variants, with c.888C &gt; T being the most prevalent among Jordanian volunteers. Novel genetic variants, including c.869A &gt; G and c.923T &gt; A, were also identified, with the latter being the most common novel variant. Haplotype analysis showed that the most prevalent <i>TMPRSS2</i> haplotype is c.911G/1051A/1052T/1010 + 45C/1011 − 38T/1011 − 52C/1011 − 54A. In silico programs predicted that <i>TMPRSS2</i> c.923T &gt; A and c.1052T &gt; A variants affect transmembrane proteins and catalytic sites.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This research provides information about the gene structure of the <i>TMPRSS2</i> binding domain in Jordanians. Some of the identified variants, especially c.923T &gt; A, may influence protein function, warranting further in vitro and in vivo investigations. In addition, further clinical research studies are needed to link the identified <i>TMPRSS2</i> variants with COVID-19 susceptibility and severity among Jordanians.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 2-3","pages":"96-105"},"PeriodicalIF":1.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891545","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":"Identifying a Genetic Link Between Lung Function and Psoriasis","authors":"Kazuya Tanimura,&nbsp;Melinda C. Aldrich,&nbsp;James Jaworski,&nbsp;Jinchuan Xing,&nbsp;Satoshi Okawa,&nbsp;Divay Chandra,&nbsp;Seyed M. Nouraie,&nbsp;Toru Nyunoya","doi":"10.1111/ahg.12587","DOIUrl":"10.1111/ahg.12587","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>The common genetic underpinnings of psoriasis and pulmonary comorbidities have yet to be explored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Material and Methods</h3>\u0000 \u0000 <p>In this cross-sectional study, we investigated the single-nucleotide polymorphisms (SNPs) associated with psoriasis and their relationship with pulmonary function using data from the UK Biobank (UKBB) and the Vanderbilt University Medical Center Biobank (BioVU).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Out of the 63 psoriasis-associated SNPs identified in previous genome-wide association studies within the European population, we successfully identified 53 SNPs, including proxy SNPs in UKBB database. Following adjustments using age and sex, 31 SNPs displayed statistically significant associations with psoriasis. Among these, 16 SNPs exhibited significant associations with forced expiratory volume in 1 s (FEV₁), 14 with forced vital capacity (FVC), and 5 with the FEV₁/FVC ratio in the UKBB. In the validation analysis using the BioVU database, 27 of the 31 psoriasis-associated SNPs were available for examination. Notably, the minor allele of SNP rs8016947 was confirmed to be significant, indicating a reduced risk for psoriasis and improved FEV₁. Similarly, the minor alleles of SNPs rs17716942 and rs8016947 were associated with a reduced risk of psoriasis and enhanced FVC. However, none of the 5 SNPs significantly associated with the FEV₁/FVC ratio in the UKBB displayed significance in the BioVU dataset.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study has unveiled genetic variants that bridge the realms of psoriasis and lung function. The genes associated with these variants, including <i>IFIH1</i>, Grancalcin gene (<i>GCA</i>), and NFKB inhibitor alpha gene (<i>NFKBIA</i>), regulate innate immune responses, which suggests that immunodysregulation, a central element in psoriasis pathogenesis, may also impact lung function, alluding to a “skin–lung axis.”</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 2-3","pages":"89-95"},"PeriodicalIF":1.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12587","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881142","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":"Intermittent episodes of acute severe encephalomyopathy and early death in two siblings caused by biallelic likely pathogenic variants in FASTKD2: Expanding phenotype and literature review","authors":"Namanpreet Kaur,&nbsp;Puneeth H. Somashekar,&nbsp;Sekar Deepha,&nbsp;Periyasamy Govindaraj,&nbsp;Anju Shukla,&nbsp;Siddaramappa J. Patil","doi":"10.1111/ahg.12585","DOIUrl":"10.1111/ahg.12585","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Combined oxidative phosphorylation (OXPHOS) deficiency 44 (COXPD44; MIM# 618855) is caused by biallelic pathogenic variants in FAS-activated serine–threonine kinase domain 2 (<i>FASTKD2)</i> (MIM# 612322). COXPD44 is characterized by variable clinical features—developmental delay, chronic epileptic encephalopathy, seizure disorder/status epilepticus and cerebellar ataxia. We ascertained one sib with episodic acute encephalomyopathy triggered by acute gastroenteritis and associated with haematological abnormalities, rhabdomyolysis leading to acute kidney injury, hypotensive shock leading to early death and a similarly affected sib with early death. Both siblings were normal neurologically in between the acute episodes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Material and Methods</h3>\u0000 \u0000 <p>Whole exome sequencing (WES) was performed in the elder sibling. Mitochondrial respiratory chain enzyme activity assaywas performed in fibroblast cells and muscle tissue of the elder sibling. Also, Adenosine triphosphate (ATP) determination assay was done in fibroblast cells of the elder sibling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>WES revealed compound heterozygous missense likely pathogenic variants in <i>FASTKD2</i>. Mitochondrial respiratory chain enzyme activity in muscle tissue showed reduced complex IV activity and ATP determination assay showed a reduction of ATP in skin fibroblasts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Herein, we report two siblings with novel clinical phenotype associated with COXPD44. Our report further validates the biallelic variants in <i>FASTKD2</i> associated with the variable phenotypes and mitochondrial OXPHOS defect.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 2-3","pages":"77-88"},"PeriodicalIF":1.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685868","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}