Spectrum Of Variants Research Articles

Spectrum of germline pathogenic variants in Brazilian hereditary breast/ovarian cancer cases.

To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT). Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven. Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with ~ 50% genotyped with a 44-gene panel and the rest with a 141-gene panel. Overall, 16.4% and 22.6% of genotyped individuals harbored PVs using 44-gene and the 141 gene panel, respectively. The most frequently mutated genes were: BRCA2 (3.7%); BRCA1 (3.6%) and monoallelic MUTYH (3.1%). The rate of PVs detected in high-risk individuals in this study was twice the 10% threshold used in Brazilian health guidelines. MGPT doubled the detection rate of PVs in cancer susceptibility genes in high-risk individuals compared with BRCA1/BRCA2 genotyping alone. The spectrum of PVs in Southern Brazil is diverse, with few recurring variants such as TP53 (0.6%), suggesting regional founder effects. The use of MGPT in hereditary cancer in Minas Gerais significantly increased the detection rate of P/LPVs compared to existing guidelines and should be considered as the primary genotyping modality in assessing hereditary cancer risk in Brazil.

Genetic screening reveals hotspot variants and prevalence rates of Hermansky-Pudlak syndrome in the Chinese population

BackgroundHermansky-Pudlak Syndrome (HPS) is a rare autosomal recessive genetic disorder associated with varied clinical manifestations, including oculocutaneous albinism, bleeding tendency, and systemic complications. Early and accurate diagnosis is crucial for medical interventions and genetic counseling. We aimed to characterize the prevalence and spectrum of pathogenic variants of HPS in the Chinese population through genetic screening of newborns. MethodsGenetic screening for HPS mutations was conducted in 29,622 Chinese newborns from 13 provinces using next-generation sequencing. Pathogenic variants were identified and classified according to ACMG guidelines. Prevalence rates were estimated, and potential hotspot variants were identified. ResultsAmong screened newborns, 215 carriers with 103 distinct pathogenic variants were identified, including two carriers with additional missense variants. Potential hotspot variants in seven genes were identified, collectively representing over 20 % of carriers in each respective gene. Particularly, the HPS3 c.1838C>G variant was exclusively reported in the Chinese population, suggesting a potential founder effect. The estimated prevalence rate of HPS in China was 2.84/1,000,000. ConclusionOur study provides valuable insights into the genetic landscape of HPS in the Chinese population, aiding in genetic counseling, early diagnosis, and management strategies. These findings contribute to enhancing the understanding and management of HPS in China.

Congenital Myasthenic Syndromes in Belgium: Genetic and Clinical Characterization of Pediatric and Adult Patients

BackgroundCongenital myasthenic syndromes (CMS) are a group of genetic disorders characterized by impaired neuromuscular transmission. CMS typically present at a young age with fatigable muscle weakness, often with an abnormal response after repetitive nerve stimulation (RNS). Pharmacologic treatment can improve symptoms, depending on the underlying defect. Prevalence is likely underestimated. This study reports on patients with CMS followed in Belgium in 2022. MethodsData were gathered retrospectively from the medical charts. Only likely pathogenic and pathogenic variants were included in the analysis. ResultsWe identified 37 patients, resulting in an estimated prevalence of 3.19 per 1,000,000. The patients harbored pathogenic variants in CHRNE, RAPSN, DOK7, PREPL, CHRNB1, CHRNG, COLQ, MUSK, CHRND, GFPT1, and GMPPB. CHRNE was the most commonly affected gene. Most patients showed disease onset at birth, during infancy, or during childhood. Symptom onset was at adult age in seven patients, caused by variants in CHRNE, DOK7, MUSK, CHRND, and GMPPB. Severity and distribution of weakness varied, as did the presence of respiratory involvement, feeding problems, and extraneuromuscular manifestations. RNS was performed in 23 patients of whom 18 demonstrated a pathologic decrement. Most treatment responses were predictable based on the genotype. ConclusionsThis is the first pooled characterization of patients with CMS in Belgium. We broaden the phenotypical spectrum of pathogenic variants in CHRNE with adult-onset CMS. Systematically documenting larger cohorts of patients with CMS can aid in better clinical characterization and earlier recognition of this rare disease. We emphasize the importance of establishing a molecular genetic diagnosis to tailor treatment choices.

Worldwide cohort study of 46, XY differences/disorders of sex development genetic diagnoses: geographic and ethnic differences in variants.

Differences/disorders of sex development (DSDs) in individuals with a 46, XY karyotype are a group of congenital disorders that manifest as male gonadal hypoplasia or abnormalities of the external genitalia. Approximately 50% of patients with 46, XY DSDs cannot obtain a molecular diagnosis. The aims of this paper were to review the most common causative genes and rare genes in patients with 46, XY DSDs, analyze global molecular diagnostic cohorts for the prevalence and geographic distribution of causative genes, and identify the factors affecting cohort detection results. Although the spectrum of genetic variants varies across regions and the severity of the clinical phenotype varies across patients, next-generation sequencing (NGS), the most commonly used detection method, can still reveal genetic variants and aid in diagnosis. A comparison of the detection rates of various sequencing modalities revealed that whole-exome sequencing (WES) facilitates a greater rate of molecular diagnosis of the disease than panel sequencing. Whole-genome sequencing (WGS), third-generation sequencing, and algorithm advancements will contribute to the improvement of detection efficiency. The most commonly mutated genes associated with androgen synthesis and action are AR, SR5A2, and HSD17B3, and the most commonly mutated genes involved in gonadal formation are NR5A1 and MAP3K1. Detection results are affected by differences in enrollment criteria and sequencing technologies.

Spectrum of rare and common mitochondrial DNA variations from 1029 whole genomes of self-declared healthy individuals from India

Mitochondrial disorders are a class of heterogeneous disorders caused by genetic variations in the mitochondrial genome (mtDNA) as well as the nuclear genome. The spectrum of mtDNA variants remains unexplored in the Indian population. In the present study, we have cataloged 2689 high confidence single nucleotide variants, small insertions and deletions in mtDNA in 1029 healthy Indian individuals. We found a major proportion (76.5 %) of the variants being rare (AF<=0.005) in the studied population. Intriguingly, we found two ‘confirmed’ pathogenic variants (m.1555 A>G and m.14484 T>C) with a frequency of ∼1 in 250 individuals in our dataset. The high carrier frequency underscores the need for screening of the mtDNA pathogenic mutations in newborns in India. Interestingly, our analysis also revealed 202 variants in our dataset which have been ‘reported’ in disease cases as per the MITOMAP database. Additionally, we found the frequency of haplogroup M (52.2 %) to be the highest among all the 18 top-level haplogroups found in our dataset. In comparison to the global population datasets, 20 unique mtDNA variants are found in the Indian population. We hope the whole genome sequencing based compendium of mtDNA variants along with their allele frequencies and heteroplasmy levels in the Indian population will drive additional genome scale studies for mtDNA. Furthermore, the identification of clinically relevant variants in our dataset will aid in better clinical interpretation of the variants in mitochondrial disorders.

A novel WNT10A variant impairs the homeostasis of alveolar bone mesenchymal stem cells

AbstractObjectivesTo explore the influence of a novel WNT10A variant on bone mineral density, proliferation, and osteogenic differentiation capacities of alveolar bone mesenchymal stem cells in humans.Subjects and MethodsWhole‐exome sequencing and Sanger sequencing were utilized to detect gene variants in a family with non‐syndromic tooth agenesis (NSTA). The panoramic mandibular index was calculated on the proband with WNT10A variant and normal controls to evaluate bone mineral density. Alveolar bone mesenchymal stem cells from the proband with a novel WNT10A variant and normal controls were isolated and cultured, then proliferation and osteogenic differentiation capacities were evaluated and compared.ResultsWe identified a novel WNT10A pathogenic missense variant (c.353A &gt; G/p. Tyr118Cys) in a family with NSTA. The panoramic mandibular index of the proband implied a reduction in bone mineral density. Moreover, the proliferation and osteogenic differentiation capacities of alveolar bone mesenchymal stem cells from the proband with WNT10A Tyr118Cys variant were significantly decreased.ConclusionsOur findings broaden the spectrum of WNT10A variants in patients with non‐syndromic oligodontia, suggest an association between WNT10A and the proliferation and osteogenic differentiation of alveolar bone mesenchymal stem cells, and demonstrate that WNT10A is involved in maintaining jaw bone homeostasis.

The expanding clinical and genetic spectrum of DYNC1H1-related disorders

Abstract Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Genetic analysis of 106 sporadic cases with hearing loss in the UAE population

BackgroundHereditary hearing loss is a rare hereditary condition that has a significant presence in consanguineous populations. Despite its prevalence, hearing loss is marked by substantial genetic diversity, which poses challenges for diagnosis and screening, particularly in cases with no clear family history or when the impact of the genetic variant requires functional analysis, such as in the case of missense mutations and UTR variants. The advent of next-generation sequencing (NGS) has transformed the identification of genes and variants linked to various conditions, including hearing loss. However, there remains a high proportion of undiagnosed patients, attributable to various factors, including limitations in sequencing coverage and gaps in our knowledge of the entire genome, among other factors. In this study, our objective was to comprehensively identify the spectrum of genes and variants associated with hearing loss in a cohort of 106 affected individuals from the UAE.ResultsIn this study, we investigated 106 sporadic cases of hearing impairment and performed genetic analyses to identify causative mutations. Screening of the GJB2 gene in these cases revealed its involvement in 24 affected individuals, with specific mutations identified. For individuals without GJB2 mutations, whole exome sequencing (WES) was conducted. WES revealed 33 genetic variants, including 6 homozygous and 27 heterozygous DNA changes, two of which were previously implicated in hearing loss, while 25 variants were novel. We also observed multiple potential pathogenic heterozygous variants across different genes in some cases. Notably, a significant proportion of cases remained without potential pathogenic variants.ConclusionsOur findings confirm the complex genetic landscape of hearing loss and the limitations of WES in achieving a 100% diagnostic rate, especially in conditions characterized by genetic heterogeneity. These results contribute to our understanding of the genetic basis of hearing loss and emphasize the need for further research and comprehensive genetic analyses to elucidate the underlying causes of this condition.

Two novel TMEM67 variations in a Chinese family with recurrent pregnancy loss: a case report

BackgroundRecurrent pregnancy loss (RPL) is a common pregnancy complication that brings great pain to pregnant women and their families. Genetic factors are an important cause reason of RPL. However, clinical research on monogenic diseases with recurrent miscarriage is insufficient.Case presentationHere we reported a Chinese family with RPL and genetic analysis of the abortion and parents. A paternally inherited heterozygous missense variant c.1415T > G (p.V472G) and a maternally inherited heterozygous nonsense variant c.2314del (p.M772*) in TMEM67 gene were identified by trio-exome sequencing. c.2314del (p.M772*) generated a premature stop codon and truncated protein, was classified as “pathogenic”. c.1415T > G (p.V472G) located in extra-cellular region, was classified as “likely pathogenic”. Biallelic variants in TMEM67 gene cause lethal Meckel syndrome 3, consistent with the proband’s prenatal phenotype.ConclusionThe current study of the Chinese family expands the pathogenic variant spectrum of TMEM67 and emphasizes the necessity of exome sequencing in RPL condition.

Novel homozygous frameshift insertion variant in the last exon of the EDARADD causing hypohidrotic ectodermal dysplasia in two siblings: case report and review of the literature

BackgroundHypohidrotic ectodermal dysplasia (HED) is a genetic disorder that results in the abnormal development of structures derived from ectodermal tissue. This rare condition predominantly affects the hair, nails, eccrine glands, and teeth. While HED can be caused by various genes, the EDA, EDAR, EDARADD, and WNT10A genes account for approximately 90% of cases. Notably, HED forms associated with variants in the EDA, EDAR, or EDARADD genes may exhibit similar phenotypes due to defects in a common signaling pathway. Proper interaction among the products of these genes is crucial for the activation of the nuclear factor (NF-κB) signaling pathway, which subsequently regulates the transcription of targeted genes. The EDARADD gene, in particular, harbors one of the rarest reported variants associated with HED.Case presentationFive-and two-years-old brothers born into consanguineous parents were examined at our outpatient medical genetics clinic at Sanliurfa Training and Research Hospital, Turkey. Both displayed the same classical phenotypic features of HED. The elder had a very sparse dark and brittle hair, sparse eyebrows and eyelashes, conical upper and lower premolar teeth with hypodontia, widely spaced teeth, very dry skin, mildly prominent forehead, and periorbital wrinkles. The younger one showed the same, but less severe, clinical features. After thorough examination and patient history evaluation, targeted next-generation sequencing analysis yielded the novel homozygous insertion variant c.322_323insCGGGC p.(Arg108ProfsTer7) in EDARADD. The mutation has not been reported to date in the literature.ConclusionsIn this report, we present two siblings exhibiting classical HED symptoms and a novel insertion variant of the EDARADD gene, which leads to a frameshift introducing a stop codon. Both brothers inherited such mutation from their parents, who were heterozygous carriers of the same variant. The present study may shed light about the pathogenic mechanisms underlying HED, and expand the spectrum of EDARADD gene variants associated with this condition.

Spectrum and characteristics of germline PALB2 pathogenic variants among patients with early-onset breast cancer in China.

e22536 Background: Partner and localizer of BRCA2 ( PALB2) plays a critical role in homologous recombination repair and recognized as a breast cancer predisposition gene. Early age at onset of breast cancer is considered a hereditary high-risk factor. However, limited information is available about early-onset breast cancer in China. The objective of this study was to investigate the spectrum and characteristics of germline PALB2 pathogenic variants among this population. Methods: A total of 1556 patients with BRCA1/2-negative early-onset breast cancer were included. Peripheral blood samples were collected and all coding regions and exon‒intron boundaries of the PALB2 genes were screened through next-generation sequencing. Results: The prevalence of germline PALB2 pathogenic variants was approximatel 0.77% in entire cohort. Eleven PALB2 pathogenic variants were identified in twelve participants, including five frameshift mutations, four nonsense mutations and one missense mutation. Except for PALB2 c.1056_1057del, which was detected twice, all other variants were detected once. In comparison to non-carriers, PALB2 carriers were more likely to be 30 years old or younger (25% vs. 14.4%), have a positive family history of breast or ovarian cancer (16.7% vs. 6.3%), exhibit metastatic lymph nodes (75% vs. 50.9%), belong to human epidermal growth factor receptor-2 (HER2) -negative and hormone receptor (HR) - positive subtype (75% vs 54.2%), and diagnosed with invasive micropapillary carcinoma (16.7% vs 3.1%). Conclusions: The prevalence of the germline PALB2 pathogenic variants is approximately 0.77% in BRCA1/2 mutation-negative early-onset breast cancer patients in China. Our findings contribute additional insights into the spectrum and characteristics of PALB2 pathogenic variants in Chinese early-onset breast cancer patients, providing valuable information for this population. Key words: PALB2, Germline mutation, Genetic sequencing, early-onset breast cancer, China. [Table: see text]

Leveraging genomic instability scores (GIS) to investigate BRCA variants of unknown significance (VUS) in ovarian cancer: An analysis of 14,513 patients in the Myriad Collaborative Research Registry (MCRR).

e17549 Background: In ovarian cancer, use of homologous recombination deficiency (HRD) and BRCA mutation ( BRCAm) status is essential in guiding PARP inhibitor (PARPi) therapy, with the greatest survival benefit in patients harboring BRCAm pathogenic variants (PVs). In other indications, PARPi are only approved for patients with BRCAm or homologous recombination repair mutations (HRRm). Genomic instability scores (GIS), an HRD proxy, are also predictive of PARPi benefit in patients without BRCAm or HRRm, suggesting that other DNA alterations without definitive classification, such as BRCA VUS or variants of Special Interpretation (SI), may be contributing to HRD. Here, we evaluated the association of BRCA VUS and SI variants that have complex clinical interpretation with reduced penetrance. Methods: Retrospective analysis was conducted using de-identified genetic testing data from the MCRR. Eligible patients with ovarian, fallopian tube or primary peritoneal cancer were tested with the MyChoice CDx HRD test between 2016 and 2023, with HRD+ defined as GIS≥42 or presence of BRCAm PV. Patient BRCAm and HRRm status were defined using the most clinically significant variant observed in BRCA1/2 and an HRR 13-gene set, respectively. GIS distributions were compared using Kolmogorov-Smirnov tests and decomposed using mixture models. Results: Overall, 31.9% (4,628/14,513) of patients were HRD+ with 9.3% (N=1,344) having BRCAm PVs. An additional 3.7% (N=538) had a BRCA VUS [N=83 uncharacterized large rearrangement (LR), N=455 non-LR]. The distributions of GIS in both non-LR and LR VUS were significantly different from the distributions in BRCAm PVs and BRCA wildtype tumors (ps &lt; 0.001), likely representing a spectrum of pathogenic and benign variants. Mixture models estimated that 28.8% [95% confidence interval (CI) 21.9, 35.8] of non-LR VUS and 55.8% (95% CI 40.0, 70.4) of LR VUS exhibited GIS similar to BRCAm PVs. Of the 15 non-LR VUS observed more than once, two were observed only in tumors with low GIS and are therefore presumed benign. BRCA SI variants (N=6) were observed in 16 patients and had a distribution of GIS significantly different from BRCA wildtype tumors (p &lt; 0.001), but not significantly different from BRCAm tumors (p = 0.1). Two SI variants had high GIS in multiple patients and are therefore presumed pathogenic. One SI variant had low GIS in two patients and is therefore presumed benign. Conclusions: The BRCA VUS GIS distribution spanned across the BRCAm PV and BRCA wildtype GIS distributions, which suggests that BRCA VUS represent a mix of benign variants and PVs. In these patients, GIS is able to correctly classify HRD status. Additional data are needed to further characterize these uncertain BRCA variants and the appropriate therapeutic and preventive strategies required for these patients.

Spectrum of genetic variants in 306 patients with non-syndromic hearing loss from Croatia

Spectrum of genetic variants in 306 patients with non-syndromic hearing loss from Croatia

Spectrum and genotype–phenotype relationship of ALPK3 variants in Chinese patients with hypertrophic cardiomyopathy

BackgroundHypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, and it has obvious genetic and clinical heterogeneity. Recently, heterozygous ALPK3 truncating variants (ALPK3tv) have been shown to cause HCM. However, the spectrum of ALPK3 variants and their relationships with the clinical characteristics of Chinese patients with HCM remain to be elucidated. Methods and resultsWhole-exome sequencing data from 986 patients with HCM and 761 controls without HCM were utilized to analyze ALPK3 variants. Eleven ALPK3tv were detected in 18 patients with HCM (1.8 %), while no such variants were identified in controls. We also detected 21 rare ALPK3 missense variants in 16 patients with HCM (1.6 %) and 8 controls (1.1 %), respectively. ALPK3tv were significantly enriched in patients with HCM (P < 0.001), whereas the prevalence of missense variants was comparable between the HCM and control groups (P = 0.309). Patients with ALPK3tv exhibited a significantly lower left ventricular outflow tract gradient (P = 0.011) and a higher prevalence of apical HCM (27.8 %; P = 0.008). ConclusionsOur study supports that heterozygous ALPK3tv, but not APLK3 missense variants, are a genetic cause of HCM. Patients with HCM carrying ALPK3tv have a greater likelihood of developing apical HCM.

Expanding the phenotypic spectrum of NOTCH1 variants: clinical manifestations in families with congenital heart disease.

Pathogenic variants in NOTCH1 are associated with non-syndromic congenital heart disease (CHD) and Adams-Oliver syndrome (AOS). The clinical presentation of individuals with damaging NOTCH1 variants is characterized by variable expressivity and incomplete penetrance; however, data on systematic phenotypic characterization are limited. We report the genotype and phenotype of a cohort of 33 individuals (20 females, 13 males; median age 23.4 years, range 2.5-68.3 years) from 11 families with causative NOTCH1 variants (9 inherited, 2 de novo; 9 novel), ascertained from a proband with CHD. We describe the cardiac and extracardiac anomalies identified in these 33 individuals, only four of whom met criteria for AOS. The most common CHD identified was tetralogy of Fallot, though various left- and right-sided lesions and septal defects were also present. Extracardiac anomalies identified include cutis aplasia (5/33), cutaneous vascular anomalies (7/33), vascular anomalies of the central nervous system (2/10), Poland anomaly (1/33), pulmonary hypertension (2/33), and structural brain anomalies (3/14). Identification of these findings in a cardiac proband cohort supports NOTCH1-associated CHD and NOTCH1-associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for NOTCH1 molecular testing (any familial CHD, simplex tetralogy of Fallot or hypoplastic left heart); (2) Cascade testing in all at-risk relatives; and (3) A thorough physical exam, in addition to cardiac, brain (structural and vascular), abdominal, and ophthalmologic imaging, in all gene-positive individuals. This information is important for guiding the medical management of these individuals, particularly given the high prevalence of NOTCH1 variants in the CHD population.

MDM2 amplification in rod-shaped chromosomes provides clues to early stages of circularized gene amplification in liposarcoma

Well-differentiated liposarcoma (WDLS) displays amplification of genes on chromosome 12 (Chr12) in supernumerary ring or giant marker chromosomes. These structures have been suggested to develop through chromothripsis, followed by circularization and breakage-fusion-bridge (BFB) cycles. To test this hypothesis, we compared WDLSs with Chr12 amplification in rod-shaped chromosomes with WDLSs with rings. Both types of amplicons share the same spectrum of structural variants (SVs), show higher SV frequencies in Chr12 than in co-amplified segments, have SVs that fuse the telomeric ends of co-amplified chromosomes, and lack interspersed deletions. Combined with the finding of cells with transient rod-shaped structures in tumors with ring chromosomes, this suggests a stepwise process starting with the gain of Chr12 material that, after remodeling which does not fit with classical chromothripsis, forms a dicentric structure with other chromosomes. Depending on if and when telomeres from other chromosomes are captured, circularized or linear gain of 12q sequences will predominate.

Features of cellular immunity in newborns with cytomegalovirus infection

Cytomegalovirus infection (CMVI) is gaining increasing significance in modern clinical medicine [1‐8]. As a cause of mortality in cases of monospecific disease origin or as a competing condition, CMVI ranks fourth after influenza, herpes, and adenovirusinfections. According to World Health Organization (WHO) data, in developing countries, 90‐100% of the population becomes infected with cytomegalovirus (CMV) during childhood [9]. The European regional bureau of WHO categorizes CMVI as a group of diseases that determine the future of infectious pathology. The relevance of CMVI is attributed to its widespread prevalence among pregnant women, high morbidity, and mortality among children, as well as a wide spectrum of clinical and pathological variants. The frequency of generalized forms of this disease, according to autopsy data, varies from 2.2% among children who died between 7 and 30 days of age to 63.4% among children who died in the first year of life.

DEPDC5 plays a vital role in epilepsy: Genotypic and phenotypic features in cohort and literature.

DEPDC5 emerges to play a vital role in focal epilepsy. However, genotype-phenotype correlation in DEPDC5-related focal epilepsies is challenging and controversial. In this study, we aim to investigate the genotypic and phenotypic features in DEPDC5-affected patients. Genetic testing combined with criteria published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), was used to identify pathogenic/likely pathogenic variants in DEPDC5 among the cohort of 479 patients with focal epilepsy. Besides, the literature review was performed to explore the genotype-phenotype correlation and the penetrance in DEPDC5-related focal epilepsies. Eight unrelated probands were revealed to carry different pathogenic/likely pathogenic variants in DEPDC5 and the total prevalence of DEPDC5-related focal epilepsy was 1.67% in the cohort. Sixty-five variants from 28 studies were included in our review. Combined with the cases reported, null variants accounted for a larger proportion than missense variants and were related to unfavorable prognosis (drug resistance or even sudden unexpected death in epilepsy; χ2 = 5.429, p = .020). And, the prognosis of probands with developmental delay/intellectual disability or focal cortical dysplasia was worse than that of probands with simple epilepsy (χ2 = -, p = .006). Besides, the overall penetrance of variants in DEPDC5 was 68.96% (231/335). The study expands the variant spectrum of DEPDC5 and proves that the DEPDC5 variant plays a significant role in focal epilepsy. Due to the characteristics of phenotypic heterogeneity and incomplete penetrance, genetic testing is necessary despite no specific family history. And we propose to adopt the ACMG/AMP criteria refined by ClinGen Sequence Variant Interpretation Working Group, for consistency in usage and transparency in classification rationale. Moreover, we reveal an important message to clinicians that the prognosis of DEPDC5-affected patients is related to the variant type and complications.

Investigating somatic variants and pathways in mismatch repair-deficient (dMMR) colorectal carcinoma in South Africa

AimsColorectal carcinoma (CRC) is a common cause of morbidity and mortality worldwide, and an emerging public health problem in sub-Saharan Africa. Several authors have described an increased frequency of mismatch...

Third-generation sequencing identified a novel complex variant in a patient with rare alpha-thalassemia

BackgroundThalassemias represent some of the most common monogenic diseases worldwide and are caused by variations in human hemoglobin genes which disrupt the balance of synthesis between the alpha and beta globin chains. Thalassemia gene detection technology is the gold standard to achieve accurate detection of thalassemia, but in clinical practice, most of the tests are only for common genotypes, which can easily lead to missing or misdiagnosis of rare thalassemia genotypes.Case presentationWe present the case of an 18-year-old Chinese female with abnormal values of routine hematological indices who was admitted for genetic screening for thalassemia. Genomic DNA was extracted and used for the genetic assays. Gap polymerase chain reaction and agarose gel electrophoresis were performed to detect HBA gene deletions, while PCR-reverse dot blot hybridization was used to detect point mutations in the HBA and HBB genes. Next-generation sequencing and third-generation sequencing (TGS) were used to identify known and potentially novel genotypes of thalassemia. We identified a novel complex variant αHb WestmeadαHb Westmeadαanti3.7/-α3.7 in a patient with rare alpha-thalassemia.ConclusionsOur study identified a novel complex variant that expands the thalassemia gene variants spectrum. Meanwhile, the study suggests that TGS could effectively improve the specificity of thalassemia gene detection, and has promising potential for the discovery of novel thalassemia genotypes, which could also improve the accuracy of genetic counseling. Couples who are thalassemia carriers have the opportunity to reduce their risk of having a child with thalassemia.