Objective:To analyze the clinical and genetic characteristics of ten Chinese pedigrees affected with 7q11.23 duplication syndrome.Methods:From December 2017 to January 2022, ten pedigrees diagnosed with 7q11.23 duplication syndrome at the First Affiliated Hospital of Zhengzhou University were enrolled as the study subjects. Clinical data of all subjects were collected, and some had subjected to copy number variation sequencing or single nucleotide polymorphism array to analyze the pattern of inheritance.Results:The probands had included six fetuses and four adolescents. Four of the six prenatal cases showed abnormal ultrasound indicators, including three with soft indicators and one with abnomal feta structural development. The clinical phenotype of the four adolescent cases had included mental retardation, delayed language development, and attention deficit hyperactivity disorder. The size of the copy number variations had ranged from 1.31 to 1.42 Mb, involving the classic region of 7q11.23 duplication syndrome. Of these, five cases had undergone parental origin testing, three cases were de novo, and two were hereditary. Conclusion:Individuals with 7q11.23 duplication syndrome may show substantial clinical phenotypic heterogeneity, hence the affected families should be provided with pre-pregnancy consultation and reproductive guidance.

Uniparental disomy (UPD)-related imprinting disorders are a group of congenital disorders which can lead to severe birth defects. Their molecular etiology is the occurrence of UPD in the genomic imprinting regions, which may cause disturbed expression of parent-of-origin imprinted genes. With the widespread applications of genetic testing techniques, the prenatal diagnosis of UPD-related imprinted diseases has gradually become clinical routines. However, due to the complicated pathogenesis of such disorders, currently there is still a lack of standards and norms for the understanding, diagnosis, management and genetic counseling. By referring to the relevant guidelines and consensus, the latest progress of research, and opinions from experts in the relevant fields, the writing group has formulated a consensus over the prenatal diagnosis and genetic counseling for UPD-related imprinting disorders, with an aim to provide a more accurate and rational evaluation in prenatal clinics.

Objective:To explore the genetic basis for a Chinese pedigree affected with Fragile X syndrome (FXS) through Nanopore long-read sequencing.Methods:A FXS pedigree who had undergone genetic counseling at the First Affiliated Hospital of Zhengzhou University in April 2023 was selected as the study subject. Nanopore long-read sequencing, triplet-repeat primed PCR (TP-PCR), methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and trinucleotide polymorphism genotyping of androgen receptor (AR) gene were used to analyze the FMR1 CGG repeat number, methylation, and X chromosome inactivation of the pedigree members. This study has been approved by the Medical Ethics Committee of the First Affiliated Hospital of Zhengzhou University (No. KS-2018-KY-36). Results:Full mutation and CpG island hypermethylation were detected in the proband. The elder sister of the proband had full mutation of the FMR1 gene on one X chromosome and hypermethylation of CpG island, while the FMR1 gene on the other X chromosome was normal. FMR1 premutation was detected in the proband′s mother. Conclusion:Nanopore long-read sequencing can simultaneously detect the dynamic mutation and methylation status of the FMR1 gene on the two X chromosomes of females, which has important value for the diagnosis of FXS in different genders.

Objective:To summarize initial experience of applying nanopore third-generation sequencing detection method (nanopore sequencing) for genetic diagnosis of non-classical 21 hydroxylase deficiency (NC 21-OHD), and to explore its performance and application prospects.Methods:Clinical data of the two NC 21-OHD patients, who were hospitalized at the First Affiliated Hospital of Zhengzhou University in May 2019, were collected. Peripheral venous blood was collected and genome DNA extracted. Genetic variants was detected by nanopore sequencing and underwent bioinformatic analysis. Pathogenetic mutations in CYP21A2 gene were validated with PCR-sanger sequencing in the two patients and their parents.Results:The average reads length and sequence depth in the patient one was 12, 792 bp and 27.19×. The average reads length and sequence depth in the patient two was 13, 123 bp and 21.34×. Compound variants of c.293-13C>G/c.844G>T (p.Val282Leu) and c.332_339delGAGACTAC (p.Gly111Valfs)/c.844G>T (p.Val282Leu) were detected in these two patients, which were consistent with clinical phenotype of NC 21-OHD. Further analysis showed that c.293-13C>G mutation was inherited from her father and c.844G>T (p.Val282Leu) mutation was inherited from her mother for the patient one. The c.844G>T (p.Val282Leu) mutation was inherited from her father and c.332_339delGAGACTAC (p.Gly111Valfs) mutation from her mother.Conclusions:The heterozygous mutations in CYP21A2 gene are the cause of NC 21-OHD in these two patients. Nanopore sequencing technique is a reliable new detection method for patients with NC 21-OHD.

OBJECTIVE: To assess the value of combined copy number variation sequencing (CNV-seq) and chromosomal karyotyping for the diagnosis of amniocytic mosaicisms, in addition with a literature review. METHODS: Forty cases of amniocytic mosaicisms detected at the Genetic and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2021, in addition with 245 mosaicisms retrieved from 11 recent literature were evaluated in terms of detection rate, consistency rate, and pregnancy outcomes. RESULTS: The detection rate of amniocytic mosaicisms was 0.46% (40/8 621) in our center. And its consistency rate with chromosomal karyotyping was 75.0% (30/40). After genetic counseling, 30 (75.0%) couples had opted to terminate the pregnancy, 5 (12.5%) had decided to continue with the pregnancy, 3 (7.5%) fetuses were born alive, and 2 cases (5.0%) were lost in touch. By contrast, 245 cases (0.39%) of mosaicisms were identified among 63 577 amniotic samples, with a consistency rate of 62.8% (103/164) with other techniques. Among these, 114 cases (55.1%) were terminated, 75 (36.2%) were born alive, and 18 (8.7%) were lost during the follow up. CONCLUSION Combined CNV-seq and chromosomal karyotyping has a high value for the detection of amniotic mosaicisms.
Pregnancy ; Female ; Humans ; Mosaicism ; Chromosome Disorders/genetics* ; DNA Copy Number Variations ; Chromosome Aberrations ; Karyotyping ; Prenatal Diagnosis/methods*

OBJECTIVE: To assess the value of copy number variation sequencing (CNV-seq) for revealing the genetic etiology of fetuses with isolated ventricular septal defect (VSD). METHODS: From December 2017 to December 2020, 69 fetuses with isolated VSD were identified at the First Affiliated Hospital of Zhengzhou University. Meanwhile, 839 similar prenatal cases were selected from public databases including Wanfang data, Wanfang Medicine, and China National Knowledge Infrastructure (CNKI) by using keywords such as "Ventricular septal defect", "Copy number variation", and "Prenatal". A total of 908 fetuses with isolated VSD were analyzed. CNV-seq was carried out for 69 fetuses. RESULTS: Among the 908 fetuses, 33 (3.63%) were found to harbor pathogenic CNVs, which included 11 chromosomal aneuploidies (1.21%) and 22 pathogenic CNVs (2.42%). The pathogenic CNVs have involved 12 genetic syndromes, with those known to involve the heart development including 5 cases of 22q11.21 deletion syndrome, 2 cases of 4q terminal deletion syndrome, and 1 case of 9q subtelomere deletion syndrome. The outcome of pregnancies for 15 fetuses with pathogenic CNVs was known, of which 12 were terminated, and 3 had spontaneous closure of the ventricular septum after birth, but 1 of them had other abnormalities. CONCLUSION Fetuses with isolated VSD have a relatively high risk for chromosomal abnormalities, for which CNV-seq should be recommended.
Female ; Pregnancy ; Humans ; DNA Copy Number Variations ; Heart Septal Defects, Ventricular/genetics* ; 22q11 Deletion Syndrome ; Fetus

Objective:To investigate the clinical phenotype and genetic characteristics of a patient with a heterozygous 6p25.3 deletion and partial trisomy 15q.Methods:A patient who had presented at the Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University on May 14, 2021 was selected as the study subject. Clinical data of the patient was collected, and G-banded chromosomal karyotyping and copy number variation sequencing (CNV-seq) were carried out.Results:The patient′s main clinical features included complete uterine septum, vaginal septum, atrophy of left eyeball, abnormal fingers and toes, and mental retardation. The karyotype of the patient was 46, XX, der(6)t(6; 15)(p25.3; q26.1). CNV-seq result has indicated a 1.20 Mb heterozygous deletion in the 6p25.3 region and a 10.20 Mb duplication in the 15q26.1q26.3 region. The deletion segment has included the FOXQ1 gene, which may be related with the abnormal development of the left eye. The duplication segment has a 96.16% overlap with the region associated with 15q26 overgrowth syndrome (including the IGF1R gene), which may be related to the patient′ s abnormal development of the Müllerian duct, abnormal fingers and toes, and mental developmental delay. Conclusion:The heterozygous deletion of the 6p25.3 region and duplication of the 15q26.1q26.3 region probably underlay the abnormal clinical phenotype in this patient.

Objective:To analyze the genetic etiology of 487 fetuses with increased nuchal translucency (NT) using copy number variant sequencing (CNV-seq) and explore the relationship between increased NT and chromosomal abnormality.Methods:A retrospective study was performed on 487 fetuses with increased NT who received CNV-seq in the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2020. These fetuses either had NT of ≥3.0-<3.5 mm (Group A, n=129) or ≥3.5 mm (Group B, n=358), the distribution and incidence of chromosomal abnormalities in the two sets of fetuses were analyzed using Chi square test or Fisher's exact test. Results:Fetuses with abnormal chromosomes accounted for 25.9%(126/487) of cases, including 107 with chromosome aneuploidy (22.0%) and 19 with pathogenic or likely pathogenic copy number variation (CNV, 3.9%). The detection rate of fetal aneuploidy in Group B was higher than that in Group A [14.0% (18/129) vs 24.9% (89/358), χ2=6.58, P=0.010]. However, no significant difference was observed regarding the detection rate of pathogenic or likely pathogenic CNV between the two groups ( χ2=0.30, P=0.584). Conclusions:The risk of fetal chromosome aneuploidy increased with NT thickness, but not with pathogenic or likely pathogenic CNV, which needed further verification due to the small sample size. CNV-seq is an option to detect the conventional detection methods for the genetic etiology of NT thickening fetuses.

OBJECTIVE: To assess the value of copy number variation sequencing (CNV-seq) and karyotyping in the prenatal diagnosis for carriers of balanced translocations. METHODS: Clinical records of 135 amniocentesis samples of balanced translocation carriers undergoing simultaneous CNV-seq and karyotyping were analyzed. Chromosomal aberrations were defined as those can definitely lead to birth defects definitely, which included chromosomal numerical abnormality, large deletion/duplication and pathogenic copy number variations (pCNVs). RESULTS: The detection rates for karyotyping and CNV-seq were 4.44% (6/135) and 5.93% (8/135) respectively, and the latter had a detection rate of 1.48(2/135) higher than the former. A total of 68 fetal chromosomal translocations were detected by karyotying analysis. CONCLUSION For couples carrying a balanced translocation, simultaneous CNV-seq and karyotyping is conducive to the detection of fetal chromosomal abnormalities and genetic counseling.
Chromosome Aberrations ; Chromosome Disorders/genetics* ; DNA Copy Number Variations ; Female ; Humans ; Karyotyping ; Pregnancy ; Prenatal Diagnosis ; Translocation, Genetic

OBJECTIVE: To explore the genetic basis for a girl with distinctive facial features, epilepsy, intellectual disability, chronic constipation and hypopigmentation of neck and upper extremities. METHODS: Whole exome sequencing was carried out for the proband. Candidate variant was verified by Sanger sequencing. RESULTS: The proband was found to harbor a heterozygous nonsense c.586G>T (p.Glu196*) variant of the ZEB2 gene, which was unreported previously. The variant was not detected in either parent. CONCLUSION The ZEB2 gene c.586G>T (p.Glu196*) variant probably underlay the Mowat-Wilson syndrome in this patient. Hypopigmentation in the neck and upper extremities may be related to Mowat-Wilson syndrome. Prenatal diagnosis was recommended for subsequent pregnancies.
Facies ; Female ; Hirschsprung Disease ; Humans ; Hypopigmentation ; Intellectual Disability/genetics* ; Microcephaly ; Pregnancy ; Zinc Finger E-box Binding Homeobox 2/genetics*