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 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 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 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 identify pathogenic variants in two families with patients suspected for Joubert syndrome(UBST) by cerebellar vermis hypoplasia. METHODS: Clinical data and peripheral venous blood and skin tissue samples were collected for the extraction of genomic DNA. Potential variants were screened by using targeted capture and next generation sequencing. Suspected variants were validated by PCR and Sanger sequencing. The frequency of the variants in the population was calculated. Pathogenicity of the variants was predicted by following the guidelines of the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was provided to these families upon subsequent pregnancy. RESULTS: The proband of family 1 was found to harbor homozygous c.2072delT (p.F691S*fs19) frameshift variant of the AHI1 gene, which may cause premature termination of translation of the Abelson helper integration site 1 after the 691st amino acid. The proband of family 2 was found to harbor compound heterozygous variants of the CPLANE1 gene, namely c.7243dupA (p.T2415Nfs*7) and c.8001delG (p.K2667Nfs*31), which can respectively lead to premature termination of translation of ciliogenesis and planar polarity effector 1 after the 2145th and 2667th amino acids. All of the three variants were previously unreported, and were predicted to be pathogenic by bioinformatic analysis. CONCLUSION The AHI1 c.2072delT and CPLANE1 c.7243dupA and c.8001delG variants probably underlay JBTS3 in family 1 and JBTS17 in family 2, respectively. Based on above results, prenatal diagnosis may be offered to the affected families upon their subsequent pregnancies.
Abnormalities, Multiple ; diagnosis ; genetics ; Adaptor Proteins, Vesicular Transport ; genetics ; Cerebellum ; abnormalities ; Eye Abnormalities ; diagnosis ; genetics ; Female ; Genetic Testing ; Genetic Variation ; Humans ; Kidney Diseases, Cystic ; diagnosis ; genetics ; Membrane Proteins ; genetics ; Mutation ; Pregnancy ; Prenatal Diagnosis ; Retina ; abnormalities

OBJECTIVE: To explore the pathogenesis of two fetuses from one family affected with Joubert syndrome (JS). METHODS: Whole exome sequencing was employed to screen potential mutations in both fetuses. Suspected mutations were verified by Sanger sequencing. Impact of intronic mutations on DNA transcription was validated by cDNA analysis. RESULTS: Two novel TCTN1 mutations, c.342-8A>G and c.1494+1G>A, were identified in exons 2 and 12, respectively.cDNA analysis confirmed the pathogenic nature of both mutations with interference of normal splicing resulting in production of truncated proteins. CONCLUSION The genetic etiology of the family affected with JS has been identified.Above findings have enriched the mutation spectrum of TCTN1gene and facilitated understanding of the genotype-phenotype correlation of JS.
Abnormalities, Multiple ; diagnosis ; genetics ; Cerebellum ; abnormalities ; Eye Abnormalities ; diagnosis ; genetics ; Humans ; Kidney Diseases, Cystic ; diagnosis ; genetics ; Membrane Proteins ; genetics ; Mutation ; Pedigree ; Retina ; abnormalities ; Whole Exome Sequencing

OBJECTIVE: To investigate the relationship between 22q11.2 duplication and clinical phenotype. METHODS: Eight fetuses with 22q11.2 duplication syndrome diagnosed by chromosome microarray analysis (CMA) through amniocentesis from February 2015 to March 2017 were enrolled in the study. The prenatal diagnostic indications, fetal ultrasound, chromosome karyotype, peripheral blood CMA results of parents, pregnancy outcomes and follow-up of postnatal growth and development were retrospectively analyzed. RESULTS: Prenatal serological screening indicated 6 cases with high risk of trisomy 21, 1 case with nuchal fold (NF) thickening and 1 case of maternal chromosomal balanced translocation. Fetal ultrasonography showed 1 case of NF thickening, 1 case of fetal cerebral ventriculomegaly and 6 cases with normal ultrasound. CMA demonstrated that the size of duplication was between 651 kb and 3.26 Mb, and 22q11.2 duplication. Parents' CMA results revealed that 6 cases inherited from one of the parents with normal phenotype, and the parents of 2 cases refused the CMA test. Two couples chose induced labor; 6 cases of continued pregnancy had normal phenotypes at birth. All 6 cases were followed up with longest of 3.5 years. The growth and psychological development were normal in 5 cases, and one case was growth retardation. CONCLUSIONS There were no specific clinical phenotypes in 22q11.2 duplication syndrome, and most of them were inherited from one parent who has normal phenotype.
Abnormalities, Multiple ; diagnosis ; genetics ; Chromosome Duplication ; genetics ; Chromosomes, Human, Pair 22 ; genetics ; DiGeorge Syndrome ; diagnosis ; genetics ; Female ; Humans ; Male ; Pregnancy ; Pregnancy Outcome ; Prenatal Diagnosis ; Retrospective Studies

Schinzel-Giedion syndrome is a rare autosomal dominant genetic disease and has the clinical features of severe delayed development, unusual facies, and multiple congenital malformations. In this case report, a 14-month-old boy had the clinical manifestations of delayed development, unusual facies (prominent forehead, midface retraction, hypertelorism, low-set ears, upturned nose, and micrognathia), and multiple congenital malformations (including cerebral dysplasia, dislocation of the hip joint, and cryptorchidism). The karyotype analysis and copy number variations showed no abnormalities, and whole exon sequencing showed a de novo heterozygous missense mutation, c.2602G > A (p. D868N), in SETBP1 gene. Therefore, the boy was diagnosed with Schinzel-Giedion syndrome. Myoclonic seizures in this boy were well controlled by sodium valproate treatment, and his language development was also improved after rehabilitation treatment. Clinical physicians should improve their ability to recognize such rare diseases, and Schinzel-Giedion syndrome should be considered for children with unusual facies, delayed development, and multiple malformations. Gene detection may help with the diagnosis of this disease.
Abnormalities, Multiple ; diagnosis ; genetics ; Craniofacial Abnormalities ; diagnosis ; genetics ; Developmental Disabilities ; diagnosis ; Face ; abnormalities ; Hand Deformities, Congenital ; diagnosis ; genetics ; Humans ; Infant ; Intellectual Disability ; diagnosis ; genetics ; Male ; Nails, Malformed ; diagnosis ; genetics

Infant hemangioma, the most common benign tumor in children, is characterized by rapid proliferation, followed by slower spontaneous involution. However, some patients with facial segmental hemangioma are associated with PHACE syndrome. PHACE syndrome is characterized by vascular nerve and vascular cutaneous lesions of multiple systemic systems, often resulting in structural and functional impairments. Recent studies have demonstrated that the possible pathogeneses of PHACE syndrome mainly include hypoxia, abnormality of mesodermal vascular endothelial cells, genetic abnormality, and abnormality of interstitial mesenchymal stem cells. The current medications for hemangioma with PHACE syndrome include beta blockers, glucocorticoids, and mTOR inhibitors. This review article mainly describes the pathogenesis, diagnoses and treatments of PHACE syndrome, in order to provide directions for diagnosis and treatment of this disorder.
Abnormalities, Multiple ; diagnosis ; etiology ; therapy ; Eye Abnormalities ; diagnosis ; etiology ; therapy ; Heart Defects, Congenital ; diagnosis ; etiology ; therapy ; Hemangioma ; diagnosis ; etiology ; therapy ; Humans ; Infant

One-year-old male Persian cat presented with multiple fractures and no known traumatic history. Marked decrease of bone radiopacity and thin cortices of all long bones were identified on radiography. Tentative diagnosis was osteogenesis imperfecta, a congenital disorder characterized by fragile bone. To determine bone mineral density (BMD), quantitative computed tomography (QCT) was performed. The QCT results revealed a mean trabecular BMD of vertebral bodies of 149.9 ± 86.5 mg/cm³. After bisphosphonate therapy, BMD of the same site increased significantly (218.5 ± 117.1 mg/cm³, p < 0.05). QCT was a useful diagnostic tool to diagnose osteopenia and quantify response to medical treatment.
Animals ; Bone Density ; Bone Diseases, Metabolic ; Cats* ; Congenital, Hereditary, and Neonatal Diseases and Abnormalities ; Diagnosis ; Fractures, Multiple ; Humans ; Male ; Osteogenesis Imperfecta ; Osteogenesis* ; Radiography