Annals of Human Genetics最新文献

ABSTRACT

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 CTSA 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 CTSA variant (NM_000308.4): c.1307A > G (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.

In recent years, numerous genetic variants have been linked with prelingual hearing loss (HL). Variants in the LOXHD1 gene (lipoxygenase homology domain—1) associated with DFNB77 are highly heterogeneous, with different auditory characteristics varying from stable to progressive and mild to profound. To date, 168 DFNB77 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., GJB2, GJB6, SLC26A4, and CDH23) 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 LOXHD1 variants in two unrelated inbred families. One is a novel homozygous pathogenic nonsense variant (c.3999C > A; p.C1333X), whereas the other is a likely pathogenic missense variant (c.6046G > 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 LOXHD1 variants identified in our study is 4.88% (2/41). This is the first LOXHD1 report associated with non-syndromic HL in South Indian families.

Introduction

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.

Methods

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.

Methods

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.

Conclusion

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.

RETRACTION: 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,” Annals of Human Genetics (Early View): https://doi.org/10.1111/ahg.12553.

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 & 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.

Introduction

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.

Methods

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.

Results

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.

Conclusion

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.

Background

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 TMPRSS2 gene may influence disease susceptibility. However, there is a lack of knowledge regarding TMPRSS2 genetic variants and haplotypes in the Jordanian population.

Aims

This study aimed to characterize the genotype and haplotype variations in the TMPRSS2 binding domain with SARS-CoV-2 among Jordanian volunteers.

Methods

The binding domain of TMPRSS2 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.

Results

The results showed significant (p < 0.05, chi-square) allele frequencies for known TMPRSS2 variants, with c.888C > T being the most prevalent among Jordanian volunteers. Novel genetic variants, including c.869A > G and c.923T > A, were also identified, with the latter being the most common novel variant. Haplotype analysis showed that the most prevalent TMPRSS2 haplotype is c.911G/1051A/1052T/1010 + 45C/1011 − 38T/1011 − 52C/1011 − 54A. In silico programs predicted that TMPRSS2 c.923T > A and c.1052T > A variants affect transmembrane proteins and catalytic sites.

Conclusions

This research provides information about the gene structure of the TMPRSS2 binding domain in Jordanians. Some of the identified variants, especially c.923T > 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 TMPRSS2 variants with COVID-19 susceptibility and severity among Jordanians.

Introduction

The common genetic underpinnings of psoriasis and pulmonary comorbidities have yet to be explored.

Material and Methods

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).

Results

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.

Conclusion

This study has unveiled genetic variants that bridge the realms of psoriasis and lung function. The genes associated with these variants, including IFIH1, Grancalcin gene (GCA), and NFKB inhibitor alpha gene (NFKBIA), 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.”

Introduction

Combined oxidative phosphorylation (OXPHOS) deficiency 44 (COXPD44; MIM# 618855) is caused by biallelic pathogenic variants in FAS-activated serine–threonine kinase domain 2 (FASTKD2) (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.

Material and Methods

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.

Results

WES revealed compound heterozygous missense likely pathogenic variants in FASTKD2. 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.

Conclusion

Herein, we report two siblings with novel clinical phenotype associated with COXPD44. Our report further validates the biallelic variants in FASTKD2 associated with the variable phenotypes and mitochondrial OXPHOS defect.

Exome sequencing (ES) may identify and report secondary findings that are unrelated to the primary disease for which the patient underwent genetic testing, but are of potential value in patient care.

In this study, we evaluated 81 American College of Medical Genetics (ACMG) medically actionable genes in 443 patients with various neurological disorders. The variants identified were classified and reported following the 2015 ACMG Standards and Guidelines for the interpretation of sequence variants and the ACMG recommendations for reporting secondary findings (v3.2).

We detected a total of 17 variants in 17 patients across 9 different genes as secondary findings. Seven heterozygous variants were found in BRCA1, MSH2, and PALB2 which are part of the cancer phenotype category. Nine heterozygous variants were found in MYH7, TTN, LDLR, DSC2, and DSP which are part of the cardiovascular phenotype category. Finally, one heterozygous variant was found in TTR which is part of the miscellaneous phenotype category. Thirteen of above mentioned variants were classified as known pathogenic and four as expected pathogenic.

The information collected in our study may lead to the prevention of severe morbidity and mortality and provides additional insight into the genetic background of the Serbian population.

Objective

This study aims to investigate the potential causal relationship, shared genomic loci, as well as potential molecular pathways and tissue-specific expression patterns between gastroesophageal reflux disease (GERD) and the risk of hospitalized/severe 2019 coronavirus disease (COVID-19).

Methods

We employed linkage disequilibrium score regression and bidirectional Mendelian randomization (MR) analysis to explore potential genetic associations between GERD (N = 602,604) and hospitalized COVID-19 (N = 2095,324) as well as severe COVID-19 (N = 1086,211). Additionally, shared genomic loci were extracted from common pivotal regions, further confirmed through corresponding colocalization analyses. GERD-driven molecular pathway network was constructed using extensive literature data mining to understand the molecular-level impacts of GERD on COVID-19.

Results

Our results revealed a significant positive genetic correlation between GERD and both hospitalized (r_g  =  0.418) and severe COVID-19 (r_g  =  0.314). Furthermore, the MR analysis demonstrated a unidirectional causal effect of genetic predisposition to GERD on COVID-19 outcomes, including hospitalized COVID-19 (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.27–1.44, p = 9.17e − 12) and severe COVID-19 (OR: 1.27, 95% CI: 1.18–1.37, p = 1.20e − 05). Additionally, GERD and both COVID-19 conditions shared one genomic locus with lead-SNPs rs1011407 and rs1123573, corresponding to the transcription factor BCL11A. Colocalization analysis further demonstrated a significant positive correlation between genome-wide association study and expression quantitative trait locus (eQTL) abnormalities, including rs1011407 (eQTL_p = 2.35e − 07) and rs1123573 (eQTL_p = 2.74e − 05). Molecular pathway analysis indicated that GERD might promote the progression of COVID-19 by inducting immune-activated and inflammation-related pathways.

Conclusion

These findings confirm that genetically determined GERD may increase the susceptibility to hospitalized/severe COVID-19. The shared genetic loci and the potential molecular pathways offer valuable insights into causal connections between GERD and COVID-19.