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Thalassemia is an autosomal recessive genetic disorder and a common form of Hemoglobinopathy. It is classified into α-thalassemia and β-thalassemia. This disease is mainly prevalent in tropical and subtropical regions, including southern China. Severe α-thalassemia and intermediate α-thalassemia are among the most common birth defects in southern China. Intermediate α-thalassemia, also known as Hb H disease, is characterized by moderate anemia. Severe α-thalassemia, also known as Hb Bart's Hydrops fetalis syndrome, is a fatal condition. Infants with severe β-thalassemia do not show symptoms at birth but develop severe anemia later, requiring expensive treatment. Most untreated patients with severe β-thalassemia die in early childhood. Screening for thalassemia carriers and genetic diagnosis in high-prevalence areas significantly reduce the incidence of severe thalassemia. This review aims to summarize the genetic diagnostic approaches for thalassemia. Conventional genetic testing methods can identify 95–98% of thalassemia carriers but may miss rare thalassemia genotypes. Third-Generation Sequencing offers significant advantages in complementing other genetic diagnostic approaches, providing a basis for genetic counseling and prenatal diagnosis. [ABSTRACT FROM AUTHOR]

Background: The collagen alpha‐1(X) chain gene (COL10A1) is a known causative gene for Schmid metaphyseal chondrodysplasia (SMCD). This study clinically examined a Chinese family (n = 42) for SMCD and inheritance pattern. Fifteen individuals were diagnosed with SMCD based on characteristic skeletal phenotypes with autosomal dominant inheritance mode. Methods: Four clinically diagnosed patients and three healthy relatives were selected for subsequent genetic tests. Trio‐whole exome sequencing (Trio‐WES) followed by Sanger sequencing and familial co‐segregation analysis were performed to identify SMCD‐associated variants. Results: COL10A1 (NM_000493.4):c.1952 G>T(p.Trp651Leu) variant was detected only in the four patients and not in the three healthy relatives. The variant was evaluated as "likely pathogenic" according to the American College of Medical Genetics and Genomics variation classification guidelines with evidence of PM2, PM5, PP1, and PP3. To test the presence of the target variant in proband's fetal offspring, we developed a noninvasive prenatal testing method by extracting cell‐free fetal DNA in maternal plasma followed by high‐depth sequencing. The variant was also detected in the fetus and later confirmed by amniocentesis. Conclusion: We identified a new disease‐causing variant in COL10A1. Cell‐free fetal DNA in maternal peripheral blood can be used as the rapid and noninvasive prenatal diagnostic method to detect the pathogenic/or likely pathogenic variant. [ABSTRACT FROM AUTHOR]

Prenatal clinical detection of thalassemia involves gap-PCR and reverse dot blot (RDB) analysis of fetal DNA acquired through invasive methods. The present study aimed to develop a non-invasive prenatal diagnostic method for thalassemia based on next-generation sequencing (NGS). A total of eight families with proband children with thalassemia were recruited for the study during a subsequent pregnancy. The sequence of the thalassemia genes of the parents and proband were determined using NGS, based on a thalassemia AmpliSeq panel. Cell-free plasma DNA from pregnant women related to the aforementioned proband was analyzed using an NGS panel, based on thalassemia-associated capture probes. Heterozygous single nucleotide polymorphisms within the 10 kb regions flanking exons of the targeted thalassemia genes were acquired using probes or AmpliSeq and employed for parental haplotype construction using Trio-based panel sequencing. The fetal haplotype was deduced from the parental haplotypes and relative haplotype dosage, and subsequently validated using gap-PCR and RDB, based on invasively sampled amniotic fluid. A non-invasive prenatal diagnosis procedure from maternal plasma fetal DNA was successfully developed based on haplotype analysis. The deduced haplotypes of eight fetuses were identical to the results of invasive prenatal diagnosis procedures, with an accuracy rate of 100%. Taken together, the present study demonstrated the potential for non-invasive prenatal diagnosis of α- and β-thalassemia using NGS and haplotype-assisted analysis. [ABSTRACT FROM AUTHOR]

Objectives: Insulin receptor substrate 1 (IRS1) is a crucial factor in the insulin signaling pathway. IRS1 gene polymorphism rs1801278 in mothers has been reported to be associated with gestational diabetes mellitus (GDM). However, it is not clear whether IRS1 gene polymorphism rs1801278 in fetuses is associated with their mothers' GDM morbidity. The purpose of this study is to analyze the association between maternal, fetal, or maternal/fetal IRS1 gene polymorphism rs1801278 and GDM risk.Design: The study was a single-center, prospective cohort study. In total, 213 pairs of GDM mothers/fetuses and 191 pairs of control mothers/fetuses were included in this study. They were recruited after they underwent oral glucose tolerance test during 24-28 weeks of gestation and followed up until delivery. All participants received the conventional interventions (diet and exercise), and no special therapy except routine treatment.Methods: A total of 213 pairs of GDM mothers/fetuses and 191 pairs of normal blood glucose pregnant mothers/fetuses were ge-notyped using PCR and DNA sequencing from January 2015 to September 2016. Maternal/fetal IRS1 gene polymorphism rs1801278 was analyzed and compared between 2 groups.Results: There were no significant differences in the frequency of individual mothers' or fetuses' IRS1 rs1801278 polymorphisms between 2 groups; if both the mothers and fetuses carried A allele, significantly lower GDM morbidity was observed in the mothers.Limitations: The sample size was relatively small as a single-center study.Conclusions: Our study suggested that maternal/fetal rs1801278 polymorphism of IRS1 is a modulating factor in GDM; both mothers/fetuses carrying the A allele of rs1801278 may protect the mothers against the development of GDM. [ABSTRACT FROM AUTHOR]