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Increased sequencing depth can improve the detection rate of noninvasive prenatal testing (NIPT) for chromosome aneuploidies and copy number variations (CNVs). However, due to the technical limitations of NIPT, false-positives and false-negatives are inevitable. False-positives for aneuploidy and CNVs have been widely reported, but few missed cases have been reported. In this study, we report 3 patients missed by NIPT, which were still missed after increasing the sequencing depth. To verify the detection efficiency of the platform, the results of NIPT in 32,796 patients treated in Yulin Women and Children Health Care Hospital from 2020 to 2022 were retrospectively analyzed. Data on false-negative cases found by postnatal follow-up or amniocentesis were collected, and the sequencing data, pregnancy examination data, and postnatal follow-up results of these missed patients were summarized. Five patients missed by NIPT were found, and they were missed again by retesting or increasing the sequencing depth. Except for hypospadias found in 1 patient, ultrasonography of the other 4 patients showed no obvious abnormalities during the whole pregnancy. Our results suggest that pregnant women should be fully informed of the benefits and limitations of NIPT before undergoing the examination to avoid unnecessary medical disputes. [ABSTRACT FROM AUTHOR]

Summary: Haemoglobin H (Hb H) disease (intermediate status of α‐thalassemia) shows marked phenotypic variability from asymptomatic to severe anaemia. Apart from the combined β‐thalassemia allele ameliorating clinical severity, reports of genetic modifier genes affecting the phenotype of Hb H disease are scarce which bring inconvenience to precise diagnosis and genetic counselling of the patients. Here, we present a novel mutation (c.948C>A, p.S316R) in the PIP4K2A gene in a female Hb H disease patient who displayed moderate anaemia and a relatively high Hb H level. Haematological analysis in her family members revealed that individuals carrying this mutation have upregulated β‐globin expression, leading to a more imbalanced β/α‐globin ratio and more Hb H inclusion bodies in peripheral red blood cells. According to functional experiments, the mutant PIP4K2A protein exhibits enhanced protein stability, increased kinase activity and a stronger regulatory effect on downstream proteins, suggesting a gain‐of‐function mutation. Moreover, introduction of the S316R mutation into HUDEP‐2 cells increased expression of β‐globin, further inhibiting erythroid differentiation and terminal enucleation. Thus, the S316R mutation is a novel genetic factor associated with β‐globin expression, and the PIP4K2A gene is a new potential modifier gene affecting the α‐thalassemia phenotype. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we aimed to identify sterility-related variants in a Chinese pedigree with male infertility and to reveal the different phenotypes and intracytoplasmic sperm injection (ICSI) outcomes of the affected members. Methods: Physical examinations were performed on male patients. G-band karyotype analysis, copy number variation sequencing, and quantitative fluorescent PCR were conducted to detect common chromosomal disorders in the probands. Whole-exome sequencing and Sanger sequencing were applied to identify the pathogenic genes and the protein expression changes caused by the very mutation were identified by Western Blot in vitro. Results: A novel nonsense mutation (c.908C > G: p.S303*) in the ADGRG2 was identified in all infertile male patients of the pedigree, which was inherited from their mothers. This variant was absent from the human genome databases. This mutation was also unexpectedly found in a male member with normal reproductive capability. Members with the mutation had different genitalia phenotypes, ranging from normal to dilated phenotypes of the vas deferens, spermatic veins and epididymis. There was a truncated ADGRG2 protein in vitro after mutation. Of the three patients' wives treated with ICSI, only one successfully gave birth. Conclusions: Our study is the first to report the c.908C > G: p.S303* mutation in the ADGRG2 in an X-linked azoospermia pedigree and is the first to report normal fertility in a member with this mutation, expanding the mutation spectrum and phenotype spectrum of this gene. In our study, ISCI had a success rate of only one-third in couples including men with azoospermia with this mutation. [ABSTRACT FROM AUTHOR]

Background: Small supernumerary marker chromosomes (sSMCs), are additional abnormal chromosomes, which can't be detected accurately by banding cytogenetic analysis. Abnormal phenotypes were observed in about 30% of SMC carriers. Duplication of chromosome 15 and related disorders, characterized by hypotonia motor delays, autism spectrum disorder (ASD), intellectual disability, and epilepsy including infantile spasms, might be account for 50% of the total sSMCs. Case presentation: An 11-month-old infant with an sSMC found by banding cytogenetics was referred to our clinic because of developmental retardation and autism spectrum disorder. After several months of rehabilitation treatment, the progress of motor development was obvious, but the consciousness was still far from satisfied. High-resolution karyotype analysis, multiplex ligation-dependent probe amplification and copy number variation sequencing (CNV-Seq) were conducted to confirm the identity of the sSMC. A bisatellited dicentric sSMC was observed clearly in high-resolution karyotype analysis and a 10.16-Mb duplication of 15q11.1q13.2 (3.96 copies) together with a 1.84-Mb duplication of 15q13.2q13.3 (3 copies) was showed by CNV-Seq in the proband. It suggested that the molecular cytogenetic karyotype was 47,XY,+dic(15;15)(q13.2;q13.3). Furthermore, the clinical symptoms of the proband mostly fit 15q duplication related disorders which are characterized by hypotonia motor delays, autism spectrum disorder (ASD), and intellectual disability. Conclusion: We reported for the first time using CNV-Seq to detect sSMCs and find a partial trisomy and tetrasomy of 15q11-q13 associated with developmental delay and autism spectrum disorder. Our report indicates that CNV-seq is a useful and economical way for diagnosis of dup15q and related disorders. [ABSTRACT FROM AUTHOR]