Annals of Human Genetics最新文献

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.

Introduction

Activation-induced cytidine deaminase (AID) deficiency is a rare autosomal recessive inborn error of immunity (IEI) characterized by increased susceptibility to infections, autoimmunity, and/or autoinflammation. AID plays an important role in immunoglobulin class switching and somatic hypermutation. AID deficiency patients have very low or absent levels of IgG, IgA, and IgE, while IgM level is elevated. The disease is designated as type 2 hyperimmunoglobulin M syndrome (HIGM-2). To date, around 130 patients with HIGM-2 have been reported, none from Egypt.

Methods

Four patients from three different consanguineous families with elevated serum IgM and low IgG and IgA were included in the study. After the exclusion of CD40 and/or CD40L deficiency by flow cytometry, patients’ samples were tested by a panel covering 452 genes (four bases PID-Pro) on the Illumina Miseq platform.

Results

All patients suffered repeated infections since childhood. Patients 1–3 had inflammatory bowel disease-like (IBD-like) symptoms, while patient 4 did not have autoimmune manifestations. Patient 1 is the first HIGM-2 patient to be reported to have renal amyloidosis as part of the autoinflammation. Patients 1–3 had the same pathogenic variant (NM_020661.4 (AID):c.406del, p.Ile136Ter), while patient 4 had another pathogenic variant (NM_020661.4 (AID):c.374G > A, p.Gly125Glu). The variant p.Ile136Ter was not reported before in any of the documented HIGM-2 patients.

Conclusion

HIGM-2 is a rare IEI that can be overlooked; hence, patients’ diagnosis is delayed. Autoimmune and autoinflammatory manifestations develop later in the disease course leading to significant morbidities. The diagnosis can be suspected after exclusion of CD40/CD40L deficiencies by flow cytometry, and the diagnosis can be confirmed by genetic testing.

Introduction

An ethics-guided decision-making framework was developed for applying pathology-supported genetic testing, a multifaceted pharmacodiagnostic approach that translates population risk stratification into clinical utility. We introduce this service, supported by the Open Genome Project, which aligns with the beneficence principle in personalized medicine.

Methods

Genetic testing of six noncommunicable disease pathways was conducted as part of a pilot program, benchmarked against a readiness checklist for implementation of genomic medicine in Africa. Patient referral criteria were determined using healthcare funder claims data, employing the Adjusted Clinical Groupers and Resource Utilization Band risk rating structure to identify potential nonresponders to treatment.

Results

Three of the 135 doctors (2.2%) invited expressed immediate disinterest in the pilot, while 24 (17.8%) actively participated. Inherited, lifestyle-triggered, and therapy-related pathologies were simultaneously assessed in case reports, with special medical scheme reimbursement tariff codes applied to 25 patient referrals. The findings were used by the participating genetic counselor to select three patients for whole exome sequencing, utilizing a novel, level-up data processing algorithm for adaptive reporting.

Conclusion

This study demonstrated the implementation of genomics into an evolving workflow for patients with a history of frequent clinic visits. Eliminating the cost barrier provided valuable insights to guide future reimbursement policy decisions.

Background

Developmental stuttering, a multifactorial speech disorder with remarkable rate of spontaneous recovery pose challenges for gene discoveries. Exonic variants in GNPTAB, GNPTG, and NAGPA involved in lysosomal pathway and AP4E1, IFNAR1, and ARMC3-signaling genes reported till date explain only ∼2.1% – 3.7% of persistent stuttering cases.

Aim

We aimed to identify additional genetic determinants of stuttering in a multiplex family by exome sequencing (n = 27) and further validation on additional extended family members (n = 21).

Materials & Methods

We employed hypothesis-free and pathway-based analyses.

Results

A novel heterozygous exonic variant NM_016256.4:c.322G > A in NAGPA with reduced penetrance and predicted pathogenicity segregated with the phenotype in a large subset of the family. Reanalysis to identify additional disease-causing variant(s) revealed exonic heterozygous variants each in RIMS2 and XYLT1 in severely affected members; and IGF2R variant in a small subset of the family. Furthermore, pathway-based analysis uncovered NM_022089.4:c.3529G > A in ATP13A2 (PARK9) in affected members; and variants in GNPTAB and GNPTG of minor significance in a few affected members.

Discussion

Genotype–phenotype correlation efforts suggest that the combined effect of gene variants at multiple loci or variants in a single gene in different subsets of the pedigree (genetic heterogeneity) may be contributing to stuttering in this family. More importantly, variants identified in ATP13A2, a Parkinson's disease gene also implicated in lysosomal dysfunction, and RIMS2 suggests for the first time a likely role of dopamine signaling in stuttering.

Conclusion

Screening for these variants in independent stuttering cohorts would be astute.

The DYNC2H1 gene has been associated with short-rib polydactyly syndrome (SRPS), among other skeletal ciliopathies. Two cases are presented of distinctive phenotypes resulting from splicing variants in DYNC2H1. The first is a 14-week-old fetus with enlarged nuchal translucency, oral hamartoma, malformed uvula, bifid epiglottis, short ribs, micromelia, long bone agenesis, polysyndactyly, heart defect, pancreatic cysts, multicystic dysplastic kidney, megabladder and trident acetabulum. A ciliopathies NGS panel revealed two compound heterozygous variants in DYNC2H1: c.7840-18T>G r.7841_7964del p.Gly2614Aspfs*5 and c.11070G>A r.11044_11116del p.Ile3682Aspfs*2. Both variants were initially classified as variants of uncertain significance but were reclassified as likely pathogenic after PCR-based RNA testing. The second is an 11-year-old overweight male with multiple accessory oral frenula, median cleft lip and alveolar ridge, polysyndactyly, brachydactyly, normal rib length, and hypogonadism. Exome sequencing revealed two compound heterozygous variants in DYNC2H1: c.6315del p.(Thr2106Glnfs*7), classified as likely pathogenic, and c.3303-16A>G p.(?), classified as a variant of uncertain significance. PCR-based RNA testing suggested that c.3303-16A>G induces an in-frame deletion: r.3303_3458del p.Asp1102_Arg1153del, although the normal transcript is still produced. These results are consistent with both SRPS type I/III in the first case and orofaciodigital syndrome in the second, an unprecedented description. This work thus improves the clinical and molecular knowledge of the phenotypes associated with splicing variants in the DYNC2H1 gene.

Objective

In this study, we aim to explore the genetic imprint of Bronze Age globalization in East Asia from a phylogeographic perspective by examining the Y-chromosome haplogroup Q1a1a-M120, and to identify key demographic processes involved in the formation of early China and the ancient Huaxia people.

Methods

Over the past few decades, we have collected the sequences of 347 Y chromosomes from the haplogroup Q1a1a-M120. These sequences were utilized to analyze and reconstruct a highly revised phylogenetic tree with age estimates. And we analyzed the geographical distribution and spatial autocorrelation of nine major sub-branches of Q1a1a-M120. Finally, we observed the expansion of Q1a1a-M120 from the beginning of the Bronze Age in East Asia, along with the continuous dissemination of its sub-lineages among East Asian populations.

Results

We suggest that certain sub-lineages played a significant role in the formation of states and early civilizations in China, as well as in the development of the ancient Huaxia people, who are the direct ancestors of the Han population. Overall, we propose that haplogroup Q-M120 played a role in the introduction of Bronze Age culture to the central region of East Asia. Therefore, it is haplogroup Q-M120, rather than the Western Eurasian paternal lineage, that expanded and contributed to the gene pool of the East Asian population.

Conclusion

In summary, the globalization of the Bronze Age led to large-scale population replacement and admixture across various regions of Eurasia; our findings highlight the unique demographic processes that occurred in East Asia during this period.

Objective

This study aimed to investigate the heritability of various obesity indices and their shared genetic factors with cardiometabolic traits in the Chinese nuclear family.

Methods

A total of 1270 individuals from 538 nuclear families were included in this cross-sectional study. Different indices were used to quantify fat mass and distribution, including body index mass (BMI), visceral fat index (VFI), and body fat percent (BFP). Heritability and genetic correlations for all quantitative traits were estimated using variance component models. The susceptibility-threshold model was utilized to estimate the heritability for binary traits.

Results

Heritability estimates for obesity indices were highest for BMI (59%), followed by BFP (49%), and VFI (40%). Heritability estimates for continuous cardiometabolic traits varied from 24% to 50%. All obesity measures exhibited consistently significant positive genetic correlations with blood pressure, fasting blood glucose, and uric acid (r_G range: 0.26–0.57). However, diverse genetic correlations between various obesity indices and lipid profiles were observed. Significant genetic correlations were limited to specific pairs: BFP and total cholesterol (r_G = 0.24), BFP and low-density lipoprotein cholesterol (r_G = 0.25), and VFI and triglyceride (r_G = 0.33).

Conclusion

The genetic overlap between various obesity indices and cardiometabolic traits underscores the importance of pleiotropic genes. Further studies are warranted to investigate specific shared genetic and environmental factors between obesity and cardiometabolic diseases.

Introduction

The American continent populations have a wide genetic diversity, as a product of the admixture of three ethnic groups: Amerindian, European, and African Sub-Saharan. Spinocerebellar ataxia type 10 (SCA10) and Huntington disease-like 2 (HDL2) have very ancient ancestral origins but are restricted to two populations: Amerindian and African Sub-Saharan, respectively. This study aimed to investigate the genetic epidemiological features of these diseases in Venezuela.

Methods

In-phase haplotypes with the expanded alleles were established in seven unrelated index cases diagnosed with SCA10 and in 11 unrelated index cases diagnosed with HDL2. The origins of remote ancestors were recorded.

Results

The geographic origin of the ancestors showed grouping in clusters. SCA10 had a minimal general prevalence of 1:256,174 families in the country, but within the identified geographic clusters, the prevalence ranged from 5 per 100,000 to 43 per 100,000 families. HDL2 had a general prevalence of 1:163,016 families, however, within the clusters, the prevalence ranged from 31 per 100,000 to 60 per 100,000 families. The locus-specific haplotype shared by all families worldwide, including the Venezuelans, supports a single old ancestral origin in each case.

Conclusion

Knowing the genetic ancestry and geographic origins of patients in Ibero-American mixed populations could have significant diagnostic implications; thus, both diseases in Venezuela should always be first explored in patients with a suggestive phenotype and ancestors coming from the same known geographic clusters.