OBJECTIVE: To analyze the phenotype and genotype of a neonate with Osteo-oto-hepato-enteric syndrome (O2HE) and review the literature. METHODS: A female neonate diagnosed with O2HE syndrome on December 13, 2024 at the First Affiliated Hospital of Zhengzhou University was selected as the study subject, and her clinical characteristics were analyzed, and pathogenic variants were explored by whole exome sequencing (WES). This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2025-KY-1038). RESULTS: The proband, a female infant, was delivered by Cesarean section at 36⁺¹ weeks of gestation. Five days after birth, she had developed severe diarrhea, mild cholestasis, sensorineural hearing loss, and growth retardation. WES revealed that she has harbored novel compound heterozygous variants c.512delA (p.Lys171Serfs*64) and c.698C>A (p.Thr233Asn) of the UNC45A gene, which were inherited from her mother and father, respectively. A total of 8 English papers were retrieved, which involved 16 patients from 14 families. Combined with our case, the 17 patients included 13 (76.5%) females and 4 (23.5%) males. Four patients (23.5%) had consanguineous parents. One case was excluded from further genetic analysis due to co-morbidity with other genetic variants. The primary clinical features included diarrhea (87.5%), cholestasis (81.3%), sensorineural hearing loss (31.3%), bone fragility (37.5%), and developmental delay (50.0%). Bi-allelic compound heterozygous mutations were identified in 12 patients (75.0%), and homozygous variants in 4 (25.0%). These included missense, nonsense, frameshift and deletional variants. The c.710T>C (p.Leu237Pro) variant was identified for 5 times, 3 of which were in homozygote forms. CONCLUSION O2HE syndrome should be suspected in cases with diarrhea, cholestasis, and hearing abnormalities during early postnatal period. Genetic testing facilitate early identification, genetic diagnosis and treatment.
Humans ; Female ; Infant, Newborn ; Male ; Mutation ; Hearing Loss, Sensorineural/genetics* ; Diarrhea, Infantile/genetics* ; Exome Sequencing ; Phenotype ; Fetal Growth Retardation ; Hair Diseases ; Facies

OBJECTIVE: To explore the genetic basis for a fetus with Cardiac-urogenital syndrome (CUGS). METHODS: A fetus with congenital heart disease identified at the Maternal Fetal Medical Center for Fetal Heart Disease, Beijing Anzhen Hospital Affiliated to Capital Medical University in January 2019 was selected as the study subject. Clinical data of the fetus was collected. Copy number variation sequencing (CNV-seq) and trio-whole exome sequencing (trio-WES) were carried out for the fetus and its parents. Candidate variants were verified by Sanger sequencing. RESULTS: Detailed fetal echocardiographic examination had revealed hypoplastic aortic arch. The results of trio-WES revealed that the fetus has harbored a de novo splice variant of the MYRF gene (c.1792-2A>C), for which both parents were of the wild-type. Sanger sequencing confirmed the variant to be de novo. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic. CNV-seq has identified no chromosomal anomalies. And the fetus was diagnosed with Cardiac-urogenital syndrome. CONCLUSION The de novo splice variant of the MYRF gene probably underlay the abnormal phenotype in the fetus. Above finding has enriched the spectrum of MYRF gene variants.
Female ; Humans ; DNA Copy Number Variations ; Fetal Diseases ; Fetus/abnormalities* ; Heart Defects, Congenital/genetics* ; Mutation ; Transcription Factors/genetics*

After the promulgation of the first edition of expert consensus on the application of chromosomal microarray analysis (CMA) technology in prenatal diagnosis in 2014, after 8 years of clinical and technical development, CMA technology has become a first-line diagnosis technology for fetal chromosome copy number deletion or duplication abnormalities, and is widely used in the field of prenatal diagnosis in China. However, with the development of the industry and the accumulation of experience in case diagnosis, the application of CMA technology in many important aspects of prenatal diagnosis, such as clinical diagnosis testimony, data analysis and genetic counseling before and after testing, needs to be further standardized and improved, so as to make the application of CMA technology more in line with clinical needs. The revision of the guideline was led by the National Prenatal Diagnostic Technical Expert Group, and several prenatal diagnostic institutions such as Peking Union Medical College Hospital were commissioned to write, discuss and revise the first draft, which was discussed and reviewed by all the experts of the National Prenatal Diagnostic Technical Expert Group, and was finally formed after extensive review and revision. This guideline is aimed at the important aspects of the application of CMA technology in prenatal diagnosis and clinical diagnosis, from the clinical application of evidence, test quality control, data analysis and interpretation, diagnosis report writing, genetic counseling before and after testing and other work specifications are elaborated and introduced in detail. It fully reflects the integrated experience, professional thinking and guidance of the current Chinese expert team on the prenatal diagnosis application of CMA technology. The compilation of the guideline for the application of CMA technology in prenatal diagnosis will strive to promote the standardization and advancement of prenatal diagnosis of fetal chromosome diseases in China.
Female ; Humans ; Pregnancy ; Asian People ; Chromosome Aberrations ; Chromosome Deletion ; Chromosome Duplication/genetics* ; DNA Copy Number Variations/genetics* ; Fetal Diseases/genetics* ; Genetic Counseling ; Microarray Analysis ; Prenatal Care ; Prenatal Diagnosis ; Practice Guidelines as Topic

OBJECTIVETo use next generation sequencing (NGS) to identify unknown abnormality of chromosome 9 in a fetus and explore its mechanism.

METHODSA pregnant woman with abnormal fetal ultrasound finding underwent amniocentesis for G-banded chromosomal analysis. Karyotyping was also performed on peripheral blood samples derived from its parents. Fetal blood sample was obtained for NGS testing to identify abnormality unrecognized by karyotyping.

RESULTSAnalysis of amniocytes has revealed a 46,XX,der(9)(?::p21 to qter) karyotype, while both parents had a normal karyotype. NGS analysis of the fetus revealed a 20.67 Mb duplication (4 454 279-25 126 275) at 9p21.3p24.2, which overlapped with that of the 9p duplication syndrome, and a 4.43 Mb deletion at 9p24.2p24.3 (10 001-4 442 364), which partially overlapped with that of 9p deletion syndrome and 46,XY sex reversal 4 region. Comparison of the sequencing data with reference genome database indicated direct duplication of 9p21.3p24.2, which was also supported by review of the morphology of chromosome 9p. Therefore, the karyotype of the fetus was verified to be 46,XX,der(9) dir dup(9)(p21.3p24.2), del(9)(p24.2p24.3).

CONCLUSIONCombined G-banded karyotyping and NGS can identify dir dup del(9p) with accuracy. Delineation of the mechanism of dir dup del(9p) and its genotype-phenotype correlation may facilitate genetic counseling and estimation of recurrence risk.

Adult ; Chromosome Banding ; Chromosome Deletion ; Chromosomes, Human, Pair 9 ; genetics ; Female ; Fetal Diseases ; diagnosis ; genetics ; Humans ; Male ; Pregnancy ; Prenatal Diagnosis ; Trisomy ; genetics

OBJECTIVETo screen for genomic copy number variants (CNVs) in a fetus with one sibling affected with Prader-Willi syndrome using single nucleotide polymorphism (SNP) array.

METHODSThe fetus and its parents were subjected to chromosomal karyotyping and SNP array analysis.

RESULTSA 5p15.33 microdeletions was identified in the fetus and its phenotypically normal mother with a size of 344 kb (113 576 to 457 213). The father was normal for both testing. Analysis of literature and CNVs database indicated the above CNV to be variant of unclear significance. The couple decided to continue with the pregnancy and gave birth to a healthy boy at full-term. No abnormalities were found during the follow-up.

CONCLUSIONThis study may provide further data for the phenotype-genotype correlation of 5p15.33 microdeletion, which differs from Cri du Chat syndrome.

Adult ; Chromosome Deletion ; Chromosomes, Human, Pair 5 ; genetics ; DNA Copy Number Variations ; Female ; Fetal Diseases ; diagnosis ; genetics ; Humans ; Male ; Prader-Willi Syndrome ; diagnosis ; embryology ; genetics ; Pregnancy ; Prenatal Diagnosis

OBJECTIVETo delineate the phenotypic characteristics of 22q11.2 deletion syndrome and the role of CRKL gene in the pathogenesis of cardiac abnormalities.

METHODSG-banded karyotyping, single nucleotide polymorphism (SNP) array and fluorescence in situ hybridization (FISH) were performed on a fetus with tetralogy of Fallot detected by ultrasound. Correlation between the genotype and phenotype was explored after precise mapping of the breakpoints on chromosome 22q11.2. SNP array was also performed on peripheral blood samples from both parents to clarify its origin.

RESULTSThe fetus showed a normal karyotype of 46,XY. SNP array performed on fetal blood sample revealed a 749 kb deletion (chr22: 20 716 876-21 465 659) at 22q11.21, which encompassed the CRKL gene but not TBX1, HIRA, COMT and MAPK1. Precise mapping of the breakpoints suggested that the deleted region has overlapped with that of central 22q11.2 deletion syndrome. SNP array analysis of the parental blood samples suggested that the 22q11.21 deletion has a de novo origin. The presence of 22q11.21 deletion in the fetus was also confirmed by FISH analysis.

CONCLUSIONCentral 22q11.21 deletion probably accounts for the cardiac abnormalities in the fetus, for which the CRKL gene should be considered as an important candidate.

Adaptor Proteins, Signal Transducing ; genetics ; Adult ; Chromosome Deletion ; Chromosomes, Human, Pair 22 ; genetics ; DiGeorge Syndrome ; diagnosis ; embryology ; genetics ; Female ; Fetal Diseases ; diagnosis ; genetics ; Genotype ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Nuclear Proteins ; genetics ; Phenotype ; Pregnancy ; Prenatal Diagnosis

OBJECTIVETo analyze mutations of IDUA gene in two pedigrees affected with mucopolysaccharidosis type I and provide prenatal diagnosis for them.

METHODSThe 14 exons of the IDUA gene were subjected to PCR amplification and Sanger sequencing.

RESULTSFor pedigree 1, the proband was found to harbor compound heterozygous mutations c.46-57delTCGCTCCTGGCC (p.Ser16_Ala19del) of exon 1 and c.1147delC (p.Arg383Alafs*57) of exon 8 of the IDUA gene, which were inherited from his father and mother, respectively. The latter was unreported previously. Prenatal diagnosis suggested that the fetus has carried a heterozygous c.46-57delTCGCTCCTGGCC mutation. For family 2, the proband was also found to carry compound mutations of the IDUA gene, namely c.721T to C (p.Cys241Arg) of exon 6 and c.1491delG (p.Thr497fs27) of exon 8, which were inherited from her mother and father, respectively. Neither mutation was reported previously. Prenatal diagnosis suggested that the fetus has carried a heterozygous c.721T to C mutation.

CONCLUSIONMutations of the IDUA gene probably underlie the MPS-I in both pedigrees. Above results have enriched the spectrum of IDUA gene mutations and facilitated prenatal diagnosis for both families.

Adult ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Child ; Child, Preschool ; China ; DNA Mutational Analysis ; Female ; Fetal Diseases ; diagnosis ; genetics ; Heterozygote ; Humans ; Iduronidase ; genetics ; Male ; Molecular Sequence Data ; Mucopolysaccharidosis I ; diagnosis ; embryology ; genetics ; Pedigree ; Pregnancy ; Prenatal Diagnosis ; Sequence Deletion

OBJECTIVETo carry out mutation analysis and prenatal diagnosis for 12 families affected with hearing loss and enlarged vestibular aqueduct from southern Zhejiang province.

METHODSClinical data and peripheral venous blood samples of 38 members from the 12 families were obtained. Mutations of 4 genes, namely SLC26A4, GJB2, c.538C to T and c.547G to A of GJB3, m.1555A to G and m.1494C to T of 12S rRNA, were detected by PCR and Sanger sequencing. Maternal contamination was excluded by application of STR detection during prenatal diagnosis.

RESULTSAmong the probands from the 12 families, 11 were found to be compound heterozygotes or homozygotes and 25 were heterozygotes. All of the families were detected with IVS7-2A to G mutations, and 4 had a second heterozygous mutation (c.2168A to G of the SLC26A4 gene). Four rare pathogenic mutations, namely IVS5-1G to A, c.946G to T, c.1607A to G and c.2167C to G, were detected in another four families. In addition, the partner of proband from pedigree 3 was identified with compound heterozygous mutations of c.235delC and c.299-300delAT, and proband of pedigree 5 has carried a mutation of c.109G to A in GJB2. For SLC26A4 gene, prenatal diagnostic testing has revealed heterozygous mutations in 6 fetuses and compound heterozygous mutations in 2 fetuses.

CONCLUSIONIVS7-2A to G and c.2168A to G of the SLC26A4 gene were the most common mutations in southern Zhejiang. Such mutations can be found in most families affected with hearing loss and enlarged vestibular aqueduct, which may facilitate genetic counseling and prenatal diagnosis for such families.

Adolescent ; Adult ; Base Sequence ; Child ; Child, Preschool ; DNA Mutational Analysis ; Female ; Fetal Diseases ; diagnosis ; genetics ; Hearing Loss ; diagnosis ; embryology ; genetics ; Hearing Loss, Sensorineural ; diagnosis ; embryology ; genetics ; Humans ; Male ; Molecular Sequence Data ; Pedigree ; Pregnancy ; Prenatal Diagnosis ; Vestibular Aqueduct ; abnormalities ; embryology ; Young Adult

OBJECTIVETo explore the value of a novel prenatal diagnosis model using combined chromosomal karyotyping and BACs-on-Beads(BoBs), a newly-developed technique.

METHODS1048 single pregnancy pregnant women with various diagnostic indications were performed amniocentesis for prenatal diagnosis with karyotyping and BoBs simultaneously.

RESULTSAmong 1047 successfully cultured specimens, 50 chromosomal abnormalities were identified with BoBs, including 43 common chromosomal trisomies, 3 chimeric chromosomes and 4 structural abnormalities, of which 3 microdeletions/microduplications were not detected with karyotyping. Except for extra yield of 1 Robertsonian translocation, the other numerical chromosomal abnormalities were detected with both karyotyping and BoBs. Ten fetal chromosome abnormalities were confirmed with karyotyping, including 8 structural abnormalities and 2 chimeric chromosomes.

CONCLUSIONCombination of karyotyping and BoBs turned out to be a rapid, complementary and effective diagnostic model for fetal chromosomal abnormalities and microdeletion syndromes, which could yield a higher detection rate of fetal chromosomal abnormalities and chromosomal microdeletions/microduplications.

Adult ; Chromosome Aberrations ; Chromosome Disorders ; diagnosis ; genetics ; Female ; Fetal Diseases ; diagnosis ; genetics ; Genetic Testing ; methods ; Humans ; Karyotyping ; instrumentation ; methods ; Male ; Pregnancy ; Prenatal Diagnosis ; instrumentation ; methods ; Young Adult

OBJECTIVETo assess the accuracy of copy number variations (CNVs) detection by non-invasive prenatal testing (NIPT) in addition to its routine targets and clinical significance of such CNVs for the reduction of fetuses born with chromosomal microdeletion/duplication syndromes.

METHODSFrom October 2014 to October 2015, 14 235 pregnant women volunteered to participate in the study. Fifteen cases detected with chromosomal CNVs by the NIPT decided to undergo prenatal diagnostic procedures including amniocentesis, G-banded karyotyping and chromosomal microarray analysis (CMA). All such cases were routinely followed up after birth.

RESULTSAmong the 14 235 subjects underwent NIPT, 18 cases were detected with Down syndrome, 4 with trisomy 18, and 2 with trisomy 13, in addition with 24 cases of CNVs. For the latter, 15 (including 11 cases with microdeletions and 4 cases with microduplications) participated in further prenatal diagnosis. In 13 cases (86.7%), the results of CMA were consistent with those of NIPT. On the other hand, only 7 out of the 15 cases showed a positive result with karyotyping, suggesting a rather high rate of missed diagnosis (46.2%). Of note, karyotyping has identified partial inversion of chromosome 9 in one case.

CONCLUSIONAs a screening tool, NIPT has a high accuracy for the detection of CNVs. However, as this method is still under improvement, it is more of a reminder rather than a diagnostic tool with full capability.

Adolescent ; Adult ; Child ; Child, Preschool ; Chromosome Aberrations ; Chromosome Banding ; Chromosome Disorders ; diagnosis ; embryology ; genetics ; DNA Copy Number Variations ; Female ; Fetal Diseases ; diagnosis ; genetics ; Humans ; Infant ; Infant, Newborn ; Karyotyping ; Male ; Microarray Analysis ; Pregnancy ; Prenatal Diagnosis ; Young Adult