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* Context.--Identification of rare thalassemia variants requires a combination of multiple diagnostic technologies. Objective.--To investigate a new approach of comprehensive analysis of thalassemia alleles based on third-generation sequencing (TGS) for identification of [alpha]- and [beta]-globin gene variants. Design.--Enrolled in this study were 70 suspected carriers of rare thalassemia variants. Routine gap-polymerase chain reaction and DNA sequencing were used to detect rare thalassemia variants, and TGS technology was performed to identify [alpha]- and [beta]-globin gene variants. Results.--Twenty-three cases that carried rare variants in [alpha]- and [beta]-globin genes were identified by the routine detection methods. TGS technology yielded a 7.14% (5 of 70) increment of rare [alpha]- and [beta]-globin gene variants as compared with the routine methods. Among them, the rare deletional genotype of-THAI was the most common variant. In addition, rare variants of CD15 (G>A) (HBA2:c.46G>A), CD117/118(+TCA) (HBA1:c.354_355insTCA), and [beta]-thalassemia 3.5-kilobase gene deletion were first identified in Fujian Province, China; to the best of our knowledge, this is the second report in the Chinese population. Moreover, HBA1:c.-24C>G, IVS-II-55 (G>T) (HBA1:c.300+55G>T) and hemoglobin (Hb) Maranon (HBA2:c.94A>G) were first identified in the Chinese population. We also identified rare Hb variants of HbC, HbG-Honolulu, Hb Miyashiro, and HbG-Coushatta in this study. Conclusions.--TGS technology can effectively and accurately detect deletional and nondeletional thalassemia variants simultaneously in one experiment. Our study also demonstrated the application value of TGS-based comprehensive analysis of thalassemia alleles in the detection of rare thalassemia gene variants. doi: 10.5858/arpa.2021-0510-OA, Thalassemia is a common inherited blood disorder resulting from deficient synthesis of globin chains. (1) According to the deficiency of globin genes, thalassemia can be classified into [alpha], [beta], [delta], [...]

Background: Pathogenic copy number variants (pCNVs) are associated with fetal ultrasound anomalies, which can be efficiently identified through chromosomal microarray analysis (CMA). The primary objective of the present study was to enhance understanding of the genotype–phenotype correlation in fetuses exhibiting absent or hypoplastic nasal bones using CMA. Methods: Enrolled in the present study were 94 cases of fetuses with absent/hypoplastic nasal bone, which were divided into an isolated absent/hypoplastic nasal bone group (n = 49) and a non‐isolated group (n = 45). All pregnant women enrolled in the study underwent karyotype analysis and CMA to assess chromosomal abnormalities in the fetuses. Results: Karyotype analysis and CMA detection were successfully performed in all cases. The results of karyotype and CMA indicate the presence of 11 cases of chromosome aneuploidy, with trisomy 21 being the most prevalent among them. A small supernumerary marker chromosome (sSMC) detected by karyotype analysis was further interpreted as a pCNV by CMA. Additionally, CMA detection elicited three cases of pCNVs, despite normal findings in their karyotype analysis results. Among them, one case of Roche translocation was identified to be a UPD in chromosome 15 with a low proportion of trisomy 15. Further, a significant difference in the detection rate of pCNVs was observed between non‐isolated and isolated absent/hypoplastic nasal bone (24.44% vs. 8.16%, p <.05). Conclusion: The present study enhances the utility of CMA in diagnosing the etiology of absent or hypoplastic nasal bone in fetuses. Further, isolated cases of absent or hypoplastic nasal bone strongly suggest the presence of chromosomal abnormalities, necessitating genetic evaluation through CMA. [ABSTRACT FROM AUTHOR]

Background: Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X‐linked dominant, lethal male disorder caused by mutations to the NSDHL (NAD(P)H steroid dehydrogenase‐like protein) gene. It primarily exhibits strictly unilateral congenital hemidysplasia with ichthyosiform erythroderma and ipsilateral limb defects in female individuals. Methods: A Chinese couple suffering from recurrent spontaneous abortion in male fetuses was enrolled in this study. Chromosomal microarray analysis and whole‐exome sequencing were performed for genetic etiological diagnosis. Results: A 33‐year‐old pregnant woman with recurrent spontaneous abortion was experiencing her third pregnancy with a male embryo. In this pregnancy, a miscarriage occurred at a gestational age of 10+6 weeks with no copy number variants. However, a novel mutation c.790‐6C>T in the NSDHL gene was observed in the fetus through whole‐exome sequencing (WES). Parental verification indicated that the NSDHL gene variant was inherited from the mother. Additionally, the variant in the NSDHL gene was absent in her subsequent pregnancy with a female fetus. Conclusion: In this study, we detected c.790‐6C>T, a novel variant in the NSDHL gene that results in recurrent miscarriage in males. Our study may broaden the scope of research on the NSDHL gene in CHILD syndrome and strengthens the application value of WES for the genetic etiological identification of recurrent miscarriage. [ABSTRACT FROM AUTHOR]

Objective: To explore the genetic etiology for a child featuring mental retardation, language delay and autism., Methods: G-banding chromosomal karyotyping and single nucleotide polymorphism array (SNP-array) were carried out for the child and her parents., Results: The child was found to have a 46,XX,dup(8p?) karyotype, for which both of her parents were normal. SNP-array revealed that the child has harbored a 6.8 Mb deletion in 8p23.3p23.1 and a 21.8 Mb duplication in 8p23.1p12, both of which were verified as de novo pathogenic copy number variants., Conclusion: The clinical features of the child may be attributed to the 8p deletion and duplication. SNP-array can facilitate genetic diagnosis for children featuring mental retardation in conjunct with other developmental anomalies.

Objective: To explore the genetic etiology for a patient featuring intellectual disability and torticollis., Methods: Peripheral blood sample was collected from the patient and subjected to G-banded karyotyping analysis and single nucleotide polymorphism array (SNP-array) assay., Results: The patient was found to have a chromosomal karyotype of 46,XX. SNP-array revealed that she has harbored a 3.8 Mb microdeletion at 10q26.3 which has encompassed 21 OMIM genes including EBF3 and ECHS1, and a 7.3 Mb duplication at 18q22.3q23 which has encompassed 19 OMIM genes including TSHZ1 and TXNL4A. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the 10q26.3 deletion was predicted to be pathogenic, whilst the 18q22.3q23 duplication was predicted to be variation of unknown significance., Conclusion: The clinical phenotype of the patient may be mainly attributed to the 10q26.3 microdeletion, and haploinsufficiency of the EBF3 gene may account for her intellectual deficiency. Above finding has provided a basis for genetic counseling for the patient.

Objective: To explore the genetic etiology of spontaneous abortions by using chromosomal microarray analysis (CMA)., Methods: Fetal tissues derived from 106 spontaneous abortion samples were subjected to CMA assay to detect genome copy number variants (CNVs)., Results: The test was successful in 94 cases (88.68%). Fifty four chromosomal abnormalities were detected, which included 44 numerical chromosomal aberrations mainly consisting of aneuploidies, triploidies and mosaicisms. Four pathogenic CNVs were detected, and two of which involved the Cri-du-chat syndrome regions. In addition, 6 chromosomal mosaicism were detected., Conclusion: Numerical chromosomal aberrations and CNVs are the main causes for early spontaneous abortions. CMA can effectively reveal the genetic etiology of spontaneous abortions. Spontaneous abortions at gestational weeks 10 to 11 +6 has the highest rate for chromosomal abnormalities, which may provide valuable information for clinical counseling.