Clinical Application of Chromosomal Microarray Analysis in Fetuses with Congenital Heart Disease

Background: Congenital heart disease (CHD) is an important birth defect, but its mechanism is still unclear. In recent years, genetic causes including chromosomal abnormalities are associated with the occurrence of congenital heart disease. In this study, CMA technology is applied to explore the genetic causes of congenital heart disease, so as to further clarify the correlation between genotype and phenotype and prepare for late pregnancy intervention and postnatal diagnosis and treatment.Objective: To explore the chromosomal abnormalities and copy number variation (CNVs) of fetuses with CHD by CMA technology, and to clarify the clinical application value of CMA technology as a detection method of first-tier antenatal CHD.Methods: Amniotic fluid sample from 155 pregnant women diagnosed with fetus CHD by prenatal ultrasound from 2018 to 2021 are collected for SNP-array detection and karyotype analysis. According to the detected CNVs results, FISH, CMA or karyotype analysis are further selected for parental verification.Results: Among the 155 fetuses with CHD, a total of 32 (20.6%) cases of chromosomal abnormalities are detected, of which 31.3% are chromosome number abnormalities. CNVs of likely pathogenicity and unknown significance are 2.5% and 5.2% respectively. The detection rate of chromosomal abnormalities in CHD of different subtypes is different, among which the high detection rate is complex CHD (31.2%), right ventricular outflow tract obstruction (30.7%) and conotruncal defects (25%). The detection rate of chromosomal abnormalities in CHD with extracardiac structural abnormalities is significantly higher than that in isolated CHD (52.4% vs 11.3%, p<0.05). In addition, the detection rate of CHD with abnormal extracardiac structure is significantly higher than that of CHD with soft markers (52.4% vs 17.8%, p<0.05), which is statistically significant. There is no significant difference in detection rate between CHD with soft markers and isolated CHD (17.8% vs 11.3%). Of the 155 pregnant women with fetus CHD, 59 chose to terminate their pregnancies, some of which were terminated according to the results of SNP-array, and some of which were terminated according to the severity of CHD.Conclusion: SNP-array technology can be used to detect chromosomal abnormalities of first-tier antenatal CHD fetuses, with high resolution, short reporting period and high efficiency. Meanwhile, pregnancy intervention can be taken according to the results.

Ischemic Stroke Genetics: What Is New and How to Apply It in Clinical Practice?

The etiology of ischemic stroke is multifactorial. Although receiving less emphasis, genetic causes make a significant contribution to ischemic stroke genesis, especially in early-onset stroke. Several stroke classification systems based on genetic information corresponding to various stroke phenotypes were proposed. Twin and family history studies, as well as candidate gene approach, are common methods to discover genetic causes of stroke, however, both have their own limitations. Genome-wide association studies and next generation sequencing are more efficient, promising and increasingly used for daily diagnostics. Some monogenic disorders, despite covering only about 7% of stroke etiology, may cause well-known clinical manifestations that include stroke. Polygenic disorders are more frequent, causing about 38% of all ischemic strokes, and their identification is a rapidly developing field of modern stroke genetics. Current advances in human genetics provide opportunity for personalized prevention of stroke and novel treatment possibilities. Genetic risk scores (GRS) and extended polygenic risk scores (PRS) estimate cumulative contribution of known genetic factors to a specific outcome of stroke. Combining those scores with clinical information and risk factor profiles might result in better primary stroke prevention. Some authors encourage the use of stroke gene panels for stroke risk evaluation and further stroke research. Moreover, new biomarkers for stroke genetic causes and novel targets for gene therapy are on the horizon. In this article, we summarize the latest evidence and perspectives of ischemic stroke genetics that could be of interest to the practitioner and useful for day-to-day clinical work.

Different Rates of the SLC26A4-Related Hearing Loss in Two Indigenous Peoples of Southern Siberia (Russia)

Hereditary hearing loss (HL) is known to be highly locus/allelic heterogeneous, and the prevalence of different HL forms significantly varies among populations worldwide. Investigation of region-specific landscapes of hereditary HL is important for local healthcare and medical genetic services. Mutations in the SLC26A4 gene leading to nonsyndromic recessive deafness (DFNB4) and Pendred syndrome are common genetic causes of hereditary HL, at least in some Asian populations. We present for the first time the results of a thorough analysis of the SLC26A4 gene by Sanger sequencing in the large cohorts of patients with HL of unknown etiology belonging to two neighboring indigenous Turkic-speaking Siberian peoples (Tuvinians and Altaians). A definite genetic diagnosis based on the presence of biallelic SLC26A4 mutations was established for 28.2% (62/220) of all enrolled Tuvinian patients vs. 4.3% (4/93) of Altaian patients. The rate of the SLC26A4-related HL in Tuvinian patients appeared to be one of the highest among populations worldwide. The SLC26A4 mutational spectrum was characterized by the presence of Asian-specific mutations c.919-2A>G and c.2027T>A (p.Leu676Gln), predominantly found in Tuvinian patients, and c.2168A>G (p.His723Arg), which was only detected in Altaian patients. In addition, a novel pathogenic variant c.1545T>G (p.Phe515Leu) was found with high frequency in Tuvinian patients. Overall, based on the findings of this study and our previous research, we were able to uncover the genetic causes of HL in 50.5% of Tuvinian patients and 34.5% of Altaian patients.

A Systematic Review to Guide Future Efforts in the Determination of Genetic Causes of Pregnancy Loss

Background: Pregnancy loss is the most common obstetric complication occurring in almost 30% of conceptions overall and in 12–14% of clinically recognized pregnancies. Pregnancy loss has strong genetic underpinnings, and despite this consensus, our understanding of its genetic causes remains limited. We conducted a systematic review of genetic factors in pregnancy loss to identify strategies to guide future research.Methods: To synthesize data from population-based association studies on genetics of pregnancy loss, we searched PubMed for relevant articles published between 01/01/2000-01/01/2020. We excluded review articles, case studies, studies with limited sample sizes to detect associations (N &lt; 4), descriptive studies, commentaries, and studies with non-genetic etiologies. Studies were classified based on developmental periods in gestation to synthesize data across various developmental epochs.Results: Our search yielded 580 potential titles with 107 (18%) eligible after title/abstract review. Of these, 54 (50%) were selected for systematic review after full-text review. These studies examined either early pregnancy loss (n = 9 [17%]), pregnancy loss &gt;20 weeks' gestation (n = 10 [18%]), recurrent pregnancy loss (n = 32 [59%]), unclassified pregnancy loss (n = 3 [4%]) as their primary outcomes. Multiple genetic pathways that are essential for embryonic/fetal survival as well as human development were identified.Conclusion: Several genetic pathways may play a role in pregnancy loss across developmental periods in gestation. Systematic evaluation of pregnancy loss across developmental epochs, utilizing whole genome sequencing in families may further elucidate causal genetic mechanisms and identify other pathways critical for embryonic/fetal survival.

Population variation in Y-chromosome microdeletion and its role in the evaluation of male infertility management: a systematic review

Background: Infertility has been a significantly growing problem worldwide, affecting approximately 10-15% of couples within reproductive age. Among the many causes of male infertility, Y-chromosome microdeletion is considered one of the most frequent genetic causes. Thus, this systematic review was constructed to determine the prevalence of Y-chromosome microdeletion and the population variations in the different types of Y-chromosome microdeletions. Methods: We searched the PubMed, Scielo, and Science Direct databases to obtain articles that addressed the frequency of Y-chromosome microdeletion and male infertility. We identified 14 articles that originated from China, India, Iran, Brazil, Indonesia, North America, South Korea, and Slovakia, and the vital information collected included the year of publication, authors, number of patients with different types of Y-chromosome microdeletions, and the proportion of microdeletion in the major affected sub-regions of the Y-chromosome. Results: In this review, we attempted to highlight the variation in the frequency of Y-chromosome microdeletion in different geographical populations. The highest and lowest frequencies of Y-chromosome microdeletion were found in Indonesian (23.94%) and Slovakian (3.5%) populations, respectively. Conclusion: In conclusion, Y-chromosome microdeletion was undeniably found to be one of the leading genetic causes of male infertility. Azoospermic factor c (AZFc) microdeletion was the most frequent type of Y-chromosome microdeletion, typically presenting in patients with various clinical manifestations that ranged from oligozoospermia to azoospermia and exhibiting the highest chance for sperm retrieval. This review will undoubtedly help clinicians in providing a more accurate consultation to their patients and determining the success rates of assisted reproductive technology.

Diagnosis of HLH: two siblings, two distinct genetic causes

This report highlights case of two siblings who developed Haemophagocytic lymphohystiocytosis (HLH) due to distinct genetic abnormalities. Though their presentation was clinically similar, the cases demonstrate that a shared genetic diagnosis among siblings cannot be assumed.

Malformation of the Brain, Skull, and Spine

Abnormal development of the central nervous system is a common cause of developmental delay and epilepsy. An understanding of central nervous system malformation begins with an overview of normal embryology. Genetic advances in embryogenesis have unfolded a complex orchestration of gene expressions in place of the traditional developmental epochs (induction, neurulation, proliferation, migration, organization, synaptogenesis, and myelination). Causes of malformation of the central nervous system are multifactorial. Genetic causes, vitamin excess or deficiency, infections, or teratogens any time during pregnancy may disturb the preprogrammed mechanisms.