OBJECTIVE: To explore the genetic etiology for a pregnant woman with a history of multiple adverse pregnancies and assess the phenotype-genotype correlation of 22q11.2 microduplication syndrome in her family. METHODS: Amniotic fluid sample was taken from a pregnant woman for whom non-invasive prenatal screening indicated chromosome 22 abnormalities in the fetus. Peripheral blood samples from the woman, her brother and parents were collected for high-throughput low-depth whole genome sequencing (CNV-seq). A pedigree traceability analysis of the results was conducted in conjunction with analysis of clinical manifestation. Relevant literature (from establishment to March 2025) was systematically searched. This study was approved by the Medical Ethics Committee of Mianyang Maternal and Child Health Care Hospital (Ethics No.: Lun Shen [2024]009). RESULTS: CNV-seq revealed that the fetus had harbored a 6.02 Mb duplication at 22q11.21q11.23. Karyotyping confirmed it as 46,X?dup(22)(q11.2). Pedigree verification demonstrated that the pregnant woman, her brother and mother had all carried the same duplication. Phenotypic analysis of the affected family members showed classic features of 22q11.2 microduplication syndrome, including hypernasal speech, low nasal bridge, congenital heart disease, and cognitive impairment. A total of 44 cases with full information (including three patients from this pedigree) were included in the analysis. The penetrance of 22q11.2 duplication was approximately 29.5% (13/44), and 52.3% (23/44) of the cases had inherited the variant from a phenotypically normal parent. CONCLUSION This study has identified the genetic basis for the woman's recurrent adverse pregnancies and phenotypic abnormalities in her family members. The scoliosis identified in her younger brother has not been previously reported, thereby may enrich the clinical phenotype of this syndrome. For fetuses identified with a 22q11.2 microduplication, detailed fetal imaging is recommended, and genetic counseling should be provided to the couples.
Humans ; Female ; Pregnancy ; Prenatal Diagnosis/methods* ; Chromosome Duplication/genetics* ; Male ; Pedigree ; DiGeorge Syndrome/diagnosis* ; Adult ; Chromosomes, Human, Pair 22/genetics* ; Abnormalities, Multiple

OBJECTIVE: To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. METHODS: Whole-exome sequencing and Sanger sequencing were carried out on 87 patients from the 46 pedigrees to analyze the variants of EXT1 and EXT2 genes. Pathogenicity of the variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). Prenatal diagnosis and preimplantation genetic testing (PGT) were provided for couples with identified pathogenic mutations. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010). RESULTS: In total 17 and 22 pathogenic variants were respectively identified in the EXT1 and EXT2 genes, among which 5 EXT1 and 12 EXT2 variants were unreported previously. Three patients with no family history were found to harbor de novo variants of the EXT1 gene. Twenty nine couples had opted for PGT or underwent prenatal diagnosis following natural conception, and 17 healthy babies were born. CONCLUSION This study has clarified the genetic etiology of 45 HME pedigrees and identified 17 novel variants, which has enriched the mutational spectrum of the EXT1 and EXT2 genes. Reproductive intervention through PGT and prenatal diagnosis have prevented the recurrence of HME in these families.
Humans ; Female ; Male ; Pedigree ; Exostoses, Multiple Hereditary/diagnosis* ; N-Acetylglucosaminyltransferases/genetics* ; Adult ; Exostosin 1 ; Asian People/genetics* ; Genetic Testing ; Exostosin 2 ; Mutation ; China ; Prenatal Diagnosis ; Pregnancy ; Genetic Counseling ; Preimplantation Diagnosis ; Exome Sequencing ; East Asian People

OBJECTIVE: To explore the genetic etiology of a Chinese pedigree with recurrent Joubert syndrome with negative results by whole-exome sequencing in the prior proband. METHODS: Chinese pedigree which opted elective abortion at the Women and Children's Hospital Affiliated to Chongqing Medical University in December 2024 was selected as the study subject. Whole-genome sequencing was carried out on fetal tissue after termination of pregnancy. Candidate variants were validated by Sanger sequencing and interpreted, while non-coding variant was analyzed using in silico prediction tools. RNA sequencing and cDNA sequencing were conducted on fetal brain tissue. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.2024YL045-02). RESULTS: Both the fetus and the affected child were found to harbor compound heterozygous variants of the CEP290 gene, namely c.7341dup (p.Leu2448fs*8) (pathogenic, maternally inherited) and c.1523-408G>A (likely pathogenic, paternally inherited). Both in silico analysis and fetal brain RNA sequencing confirmed aberrant RNA splicing caused by the intronic variant. CONCLUSION This case has highlighted the value of combining whole-genome sequencing with RNA functional validation. Above results not only enriched the spectrum of CEP290 gene mutations but also underscored its diagnostic value in resolving complex prenatal cases, providing critical clues for the prenatal diagnosis and recurrence risk assessment in genetic counseling.
Female ; Humans ; Pregnancy ; Abnormalities, Multiple/genetics* ; Antigens, Neoplasm/genetics* ; Cell Cycle Proteins/genetics* ; Cerebellum/abnormalities* ; Cytoskeletal Proteins/genetics* ; Eye Abnormalities/genetics* ; Introns/genetics* ; Kidney Diseases, Cystic/diagnosis* ; Pedigree ; Retina/abnormalities* ; Sequence Analysis, RNA/methods* ; Whole Genome Sequencing/methods* ; Child

OBJECTIVE: To explore the clinical and genetic characteristics of fetuses with Kabuki syndrome (KS) and their genotype-phenotype correlation. METHODS: A retrospective analysis was carried out on the prenatal manifestations and results of genetic testing of six KS fetuses diagnosed by whole-exome sequencing (WES). The findings were compared with 28 prenatally diagnosed KS cases reported in the literature to summarize the prenatal features of KS. This study has been approved by the Ethics Committee of Maternal and Child Health Care Hospital of Hubei Province (Ethics No.: 2025-141-01). RESULTS: Prenatal ultrasound findings in KS fetuses showed high heterogeneity. The most common abnormalities were cardiac (23/35, 65.7%) and renal (20/35, 57.1%), which are often accompanied by amniotic fluid abnormalities (5/35, 14.3%), single umbilical artery (5/35, 14.3%), and fetal hydrops (4/35, 11.4%). Among the six fetuses from our center, all were identified by WES to harbor pathogenic variants of the KMT2D gene, and all of which were de novo. These included 3 frameshift variants, 2 nonsense variant, and 1 missense variant, among which 4 were unreported previously. CONCLUSION This study has expanded the mutational spectrum of the KMT2D gene. Prenatal ultrasound findings of KS lack specificity, though multi-system anomalies or specific soft markers may indicate KS. WES is an effective tool for the diagnosis, and KS should be included in the differential diagnosis list for prenatal cardiac and renal abnormalities.
Humans ; Hematologic Diseases/diagnostic imaging* ; Face/diagnostic imaging* ; Female ; Vestibular Diseases/diagnostic imaging* ; Abnormalities, Multiple/diagnostic imaging* ; Pregnancy ; Ultrasonography, Prenatal ; Adult ; Neoplasm Proteins/genetics* ; Retrospective Studies ; DNA-Binding Proteins/genetics* ; Male ; Exome Sequencing ; Fetus/diagnostic imaging* ; Genetic Association Studies ; Mutation

OBJECTIVE: To explore the clinical characteristics and genetic etiology of a patient with Fliedner-Zweier syndrome (FZS). METHODS: A pregnant woman who was diagnosed with FZS at the Affiliated Women and Children's Hospital of Ningbo University in November 2023 for "intellectual disability, epilepsy, delayed language development and facial abnormalities" was selected as the study subject. Peripheral blood samples were collected from the woman and her husband, whilst amniotic fluid sample was obtained from the fetus. Following extraction of genomic DNA, whole-exome sequencing (WES) and chromosomal karyotyping analysis were performed. Candidate variant was validated by Sanger sequencing. Pathogenicity of the variant was classified based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2023-094). RESULTS: The proband, a 23-year-old woman, was at 19⁺² weeks of gestation and had a history of epilepsy, mild intellectual disability, delayed language development, and subtle facial dysmorphism. Chromosomal analysis showed the she has a normal karyotype. WES revealed that the woman and her fetus both harbored a heterozygous c.1489C>T (p.Gln497Ter) nonsense variant of the SCAF4 gene, which was verified by Sanger sequencing as de novo. Based on the ACMG guidelines, the variant was classified as pathogenic (PVS1+PM2_supporting+PS2_supporting). According to pre-set search strategy, five articles were retrieved. Together with the patient in this study, a total of 69 FZS patients were involved (including 7 from China). The main clinical features have included intellectual disability, epilepsy, behavioral abnormalities, and facial dysmorphism. CONCLUSION The heterozygous c.1489C>T (p.Gln497Ter) variant of the SCAF4 gene probably underlyay the FZS in this patient. Above finding has expanded the mutational spectrum of the SCAF4 gene.
Humans ; Female ; Intellectual Disability/genetics* ; Pregnancy ; Young Adult ; Exome Sequencing ; Epilepsy/genetics* ; Abnormalities, Multiple/genetics* ; Mutation ; Karyotyping

OBJECTIVE: To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome. METHODS: Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2. RESULTS: The proband of pedigree 1 was a fetus at 23⁺⁵ weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up. CONCLUSION The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.
Female ; Humans ; Pregnancy ; Pedigree ; Cerebellum/abnormalities* ; Abnormalities, Multiple/diagnosis* ; Eye Abnormalities/diagnosis* ; Kidney Diseases, Cystic/diagnosis* ; Phosphoric Monoester Hydrolases/genetics* ; Retina/abnormalities* ; East Asian People ; Mutation

OBJECTIVE: To explore the genetic basis for a fetus with limb abnormality and cardiac malformation. METHODS: Clinical data of a fetus diagnosed at the Shandong Provincial Maternal and Child Health Care Hospital on April 30th, 2021 was collected. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. X-inactivation analysis was carried out for the female members of its family. RESULTS: The fetus was found to have meningoencephalocele, absence of bilateral radii, cleft lip, abnormal great arteries, and single umbilical artery at the gestational age of 11+ weeks. Sequencing revealed that the fetus has harbored a hemizygous c.1162del (p.Y388Tfs*7) variant of the FANCB gene, which was maternally inherited. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and ClinGen, the variant was classified as pathogenic (PVS1+PM2_Supporting+PP4). X-inactivation analysis has revealed complete skewed X-inactivation in the pregnant woman and her mother. CONCLUSION The hemizygous c.1162del (p.Y388Tfs*7) variant of the FANCB gene probably underlay the multiple malformations in this fetus.
Female ; Humans ; Pregnancy ; Abnormalities, Multiple ; Cleft Lip ; Fanconi Anemia Complementation Group Proteins ; Fetus ; Gestational Age ; Mothers

OBJECTIVE: To explore the genetic basis for a fetus with multiple malformations. METHODS: Clinical data of the fetus was collected, Amniotic fluid sample of the fetus was subjected to conventional G-banded karyotyping, low-depth whole genome copy number variants detection and whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing of the fetus and its parents. RESULTS: Prenatal ultrasound scan at 21⁺⁵ gestational weeks had revealed increased nuchal thickness (9.0 mm), enhanced echos of bilateral renal parenchyma, seroperitoneum, left pleural effusion and right displacement of the heart. The mother had a previous history of terminated pregnancy for multiple fetal anomalies. No abnormality was found by conventional karyotyping and CNV analysis, though WES revealed that the fetus has harbored a de novo heterozygous c.607C>T (p.Arg203Trp) variant of the ACS1 gene (NM_018026.3), and the result was validated by Sanger sequencing. CONCLUSION Through WES and prenatal ultrasonography, the fetus was diagnosed with Schuurs-Hoeijmakers syndrome due to the heterozygous c.607C>T (p.Arg203Trp) variant of the PACS1 gene (NM_018026.3). For fetuses with multiple malformations, WES can help to reveal the genetic etiology when CNV result is negative.
Female ; Pregnancy ; Humans ; Prenatal Diagnosis ; Ultrasonography, Prenatal ; Syndrome ; Fetus ; Abnormalities, Multiple ; Vesicular Transport Proteins

OBJECTIVE: To explore the clinical and genetic characteristics of a fetus with Melnick-Needles syndrome (MNS). METHODS: A fetus with MNS diagnosed at Ningbo Women and Children's Hospital in November 2020 was selected as the study subject. Clinical data was collected. Pathogenic variant was screened by using trio-whole exome sequencing (trio-WES). Candidate variant was verified by Sanger sequencing. RESULTS: Prenatal ultrasonography of the fetus had shown multiple anomalies including intrauterine growth retardation, bilateral femur curvature, omphalocele, single umbilical artery, and oligohydramnios. Trio-WES revealed that the fetus has harbored hemizygous c.3562G>A (p.A1188T) missense variant of the FLNA gene. Sanger sequencing confirmed that the variant was maternally derived, whilst its father was of a wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS4+PM2_Supporting+PP3+PP4). CONCLUSION The hemizygous c.3562G>A (p.A1188T) variant of the FLNA gene probably underlay the structural abnormalities in this fetus. Genetic testing can facilitate accurate diagnosis of MNS and provide a basis for genetic counseling for this family.
Child ; Female ; Humans ; Pregnancy ; Abnormalities, Multiple/genetics* ; Fetal Growth Retardation ; Fetus ; Filamins/genetics* ; Genetic Counseling ; Mutation ; Osteochondrodysplasias

Pregnancy ; Female ; Humans ; Live Birth ; Calcium ; Oocytes ; Pregnancy, Multiple ; Pregnancy Rate ; Retrospective Studies ; Fertilization in Vitro ; Oocyte Retrieval