[Prenatal diagnosis and genetic analysis of a rare case with 8p deletion and duplication].

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.

[Clinical and genetic analysis of a patient with 10q26.3 microdeletion in conjunct with 18q22.3q23 microduplication].

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.

[Application of chromosomal microarray analysis in the diagnosis of genetic etiology of spontaneous abortions].

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.

[The value of combined detection of HbA2 and HbF for the screening of thalassemia among individuals of childbearing ages].

OBJECTIVE: To assess the application value of combined detection of HbA2 and HbF for the screening of thalassemia among a population of childbearing age in Quanzhou, Fujian, and determine the optimal cut-off values for the region. METHODS: Capillary hemoglobin electrophoresis and genetic testing for α and ß globin gene mutations were simultaneously carried out on 11 428 patients with suspected thalassemia. Statistical methods were used to analyze the distribution of various types of thalassemia and compare the performance of HbA2 and HbF measurement for the screening of various types of thalassemia. The optimal cut-off values for HbA2 and HbF were determined with the ROC curves. RESULTS: 4591 patients with α, ß, and αß compound thalassemia were identified by genetic testing. The most common genotypes for α and ß thalassemia included --SEA/αα and ß654/ßN, ß41-42/ßN, and ß17/ßN. The ROC curves were drawn to compare the performance of HbA2 screening for α-, ß-, αß-compound, static α-, mild α-, and intermediate α-thalassemia, and the maximum area under the curves was 0.674, 0.984, 0.936, 0.499, 0.731, 0.956, and the optimal cut-off values for HbA2 were 2.45%, 3.25%, 3.65%, 2.95%, 2.55%, 1.75%, respectively. CONCLUSION: HbA2 is an efficient indicator for identifying intermediate types of α-, ß-, and αß compound thalassemia. The combination of HbA2 and HbF measurement can effectively detect carriers for ß-thalassemia mutations.

[Genetic analysis of a case with a supernumerary marker derived from chromosome 9].

OBJECTIVE: To delineate a small supernumerary marker chromosome (sSMC) derived from chromosome 9 with combined cytogenetic and molecular methods. METHODS: For a pregnant woman with fetal ultrasound revealing left ventricular punctate hyperechoic echo, and a high risk for monosomy or partial deletion of chromosome 8, chromosome 9 trisomy, monosomy or partial deletion of chromosome 11 by non-invasive prenatal testing, and an abnormal MOM value revealed by mid-term serum screening, amniocentesis was performed for G banded chromosomal analysis and single nucleotide polymorphism array (SNP-array) assay. Peripheral blood samples of the woman and her spouse were also collected for the above tests. In addition, the woman was further subjected to C banding karyotyping analysis and fluorescence in situ hybridization (FISH) assay. RESULTS: The G-banded karyotype of the pregnant women was 47,XX,+mar[20]/46,XX[80], whilst C-banding analysis showed a deep stain in the middle of the sSMC (suggestive of centromeric region) and light stain at both ends (suggestive of euchromatism). FISH combined with DAPI banding analysis using 9pter/9qter probes revealed a karyotype of 47,XX,+mar.ish i(9)(9p10)(9p++)[2]/46,XX[18], whilst SNP-array has revealed a 68.1 Mb duplication in the 9p24.3q13 region. A database search has suggested the duplication to be likely pathogenic. No abnormality was found in her fetus and spouse by karyotyping and SNP-array analysis. CONCLUSION: Through combined cytogenetic and molecular genetic analysis, a sSMC derived from chromosome 9 was delineated, which has enabled genetic counseling for the couple.

Application of the BACs-on-Beads assay for the prenatal diagnosis of chromosomal abnormalities in Quanzhou, China.

BACKGROUND: An increasing number of techniques have been used for prenatal diagnosis of genetic abnormalities. Our initial objective was to explore the value of the BACs-on-Beads (BoBs) assay for the prenatal diagnosis of aneuploidies and microdeletion/microduplication syndromes in Quanzhou, Southeast China. METHODS: A total of 1409 pregnant women with high-risk factors for chromosomal abnormalities admitted to Quanzhou Women's and Children's Hospital were enrolled in this study. BoBs assays and karyotype analyses were conducted for all subjects. Subsequently, chromosome microarray analysis (CMA) or fluorescence in situ hybridization (FISH) was performed to validate the findings. RESULTS: In this study, karyotype analysis and BoBs assay failed in 4 cases, and 2 cases, respectively. A total of 1403 cases were successfully analyzed, with success rates of 99.72% (1405/1409) and 99.85% (1407/1409) for karyotype analysis and Bobs assay, respectively. BoBs assay rapidly detected chromosomal aneuploidies in line with the karyotyping data. Additionally, 23 cases of microdeletions/microduplications were detected by BoBs assay but missed by karyotyping, including 22q11.2 microdeletions/microduplications, 5p15.32p15.33 microdeletion, Xp22.31 microdeletions/microduplications, Xq27.3 microdeletion, and Yp11.2 and Yq11.22q11.222 microduplication. In comparison with karyotyping, fewer mosaicisms were identified by BoBs assay. A high detection rate of chromosomal abnormalities was observed in the high-risk group during noninvasive prenatal testing (NIPT) (41.72%) and the abnormal ultrasound group (13.43%). CONCLUSIONS: BoBs assay can be used for the rapid and efficient prenatal diagnosis of common aneuploidies and microdeletion/microduplication syndromes. Moreover, the combined use of BoBs assay and karyotyping in prenatal diagnosis may allow for a more effective detection of chromosomal abnormalities.

[A case of neonatal Cornelia de Lange syndrome caused by a novel variant of SMC1A gene].

OBJECTIVE: To explore the genetic etiology of a neonate with suggestive features of Cornelia de Lange Syndrome (CdLS). METHODS: Chromosome karyotyping, copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) were carried out for the child. Meanwhile, peripheral venous blood samples were taken from his parents for verifying the suspected pathogenic variants detected in the child. RESULTS: The child has exhibited developmental delay, microcephaly, ptosis, micrognathia, and low ear setting, and was suspected as CdLS. No abnormality was found by karyotyping and CNV-seq analysis. WES has detected 5 heterogeneous variants and 1 hemizygous variant on the X chromosome. Combining the genetic pattern and result of family verification, a hemizygous C.3500T>C (p.ile1167thr) of the SMC1A gene was predicted to underlay the clinical manifestations of the patient. This variant was not recorded in the dbSNP and gnomAD database. PolyPhen2, Provean, SIFT all predicted the variant to be harmful, and PhastCons conservative prediction is was a conservative mutation. ACMG variant classification standard evidence supports are PM2, PP2, and PP3. CONCLUSION: The novel c.3500T>C (p.Ile1167Thr) missense mutation of the SMC1A gene probably underlay the genetic etiology of CdLS in this child. Above results has enriched the mutation spectrum of CdLS type II, and facilitated clinical counseling for this family.

[Non-invasive prenatal testing and genetic diagnosis of a case of Pallister-Killian syndrome].

OBJECTIVE: To apply combined non-invasive prenatal testing (NIPT), chromosomal karyotyping and chromosomal microarray for the screening and prenatal diagnosis of a fetus with supernumerary small marker chromosome (sSMC). METHODS: Standard NIFTY and full gene NIFTY kits were applied to detect free DNA (cfDNA) isolated from peripheral blood sample of a pregnancy woman. Amniocentesis was carried out for the woman for an abnormal NIPT result. G-banded karyotyping and single nucleotide polymorphism array (SNP array) were used to determine the karyotype and copy number variants in the fetus. The result was validated with a fluorescence in situ hybridization (FISH) assay. RESULTS: Both the standard NIFTY and full gene NIFTY indicated abnormal dup(chr12:707 334-33 308 759), for which the T score value of copy number anomaly in full gene NIFTY is 6.823, which is higher than the standard NIFTY's T-score value of 3.9535. The two NIFTY results were both above the normal threshold ± 3. Conventional G-banding analysis of amniocytes showed that the fetus has a karyotype of 47,XY,+mar. SNP-array delineated duplication of 12p (arr [hg19]12p13.33p11.1 (173 786_34 385 641)× 4, which was verified by FISH. Based on the above results, the fetus was diagnosed as a novel case of Pallister-Killian syndrome. CONCLUSION: NIPT has a certain value for the prenatal detection of PKS. Combined use of multiple techniques can facilitate delineation of the source of sSMC.

[Molecular genetic analysis of a child with de novo 16p11.2 microdeletion].

OBJECTIVE: To explore the genetic basis for a child featuring developmental delay, intelligent disability and language deficit. METHODS: Peripheral blood samples of the child and her parents were collected for routine G-banding karyotyping analysis and single nucleotide polymorphism array (SNP array) detection. Amniotic fluid was also sampled from the mother for karyotyping analysis and SNP array detection. RESULTS: No karyotypic abnormality was found with the child and her parents. SNP array showed that the child has carried a 761.4 kb microdeletion at 16p11.2, while her mother has carried a 444.4 kb microduplication at 15q13.3. Her father's result was negative. Further analysis showed that the 15q13.3 microduplication was inherited from her maternal grandfather who was phenotypically normal. Prenatal diagnosis showed that the fetus has inherited the15q13.3 microduplication from its mother. CONCLUSION: The child has carried a de novo 16p11.2 microdeletion, which overlaps with 16p11.2 microdeletion syndrome region, in addition with similar clinical phenotypes. The 16p11.2 microdeletion probably underlies her abnormal phenotype.

[Clinical and genetic study of a child with 15q11.2 microduplication].

OBJECTIVE: To explore the genetic basis of a child with developmental delay and intellectual disability. METHODS: Peripheral blood samples of the child and his parents were collected for routine G-band karyotyping analysis and single nucleotide polymorphism array (SNP array) assay. Amniotic fluid sample was collected during the next pregnancy for prenatal diagnosis. RESULTS: No karyotypic abnormality was found in the child and his parents. SNP array showed that the child has carried a 855.3 kb microduplication in 15q11.2. His mother carried the same duplication but had no phenotypic anomaly. No microdeletion/microduplication was found in his father. Upon prenatal diagnosis, no abnormalities was found with the chromosomal karyotype and SNP array result of the fetus. CONCLUSION: 15q11.2 microduplication may result in developmental delay and intellectual disability, for which CYFIP1 may be a candidate gene. However, the duplication may increase the risk but with a low penetrance. This should attract attention during clinical consultation.

Molecular analysis of a large novel deletion causing α+-thalassemia.

BACKGROUND: α-thalassaemia is an inherited blood disorder caused by mutations in the α-globin gene cluster. Recognizing the pathogenic α-globin gene mutations associated with α-Thalassemia is of significant importance to thalassaemia's diagnosis and management. METHODS: A family with α-thalassaemia from Fujian, China was recruited for this study. The phenotype was confirmed through haematological analysis. Commercially available Gap-PCR genotypic methods were employed to identify the known deletions causing α-thalassemia. MLPA analysis was used to study the novel mutations; this was then confirmed through DNA sequencing and bioinformatics analysis. RESULTS: The proband of the family belonged to Southeast Asian type (--SEA) thalassaemia. None of the known mutations associated with α-thalassaemia were detected in this family's genetics, whereas a novel 6.9 kb deletion (16p13.3 g.29,785-36,746) covering the α2 gene on the globin gene cluster was identified with MLPA and confirmed through Sanger Sequencing. This data led us to propose a novel pathogenic deletion associated with α-thalassemia: -α6.9 /--SEA. CONCLUSIONS: A novel α-thalassaemia deletion was identified in members of a Chinese family and subsequently analyzed. This finding has helped broaden the spectrum of pathogenic mutations leading to the development of α-thalassaemia, paving the way for improved disease diagnosis and management.

[Analysis a family with partial Xq deletion].

OBJECTIVE: To analyze partial deletion of the long arm of X chromosome in a family and explore the mechanism underlying its phenotypes. METHODS: G-banding technique was employed to analyze the karyotypes of the subjects, and fluorescence in situ hybridization (FISH) was used to analyze their X chromosomes with Xpter, Xqter and WCPX probes. RESULTS: The karyotypes of the proband, her mother and her fetus were all 46,X,del(X)(q24). Combined FISH and karyotyping analysis suggested that the proband and her fetus both carried a Xq24q27.3 deletion. CONCLUSION: The Xq24q27.3 deletion carried by the family is closely related with premature ovarian failure but not with short stature, gonadal dysgenesis and primary amenorrhea.

A First Clinical and Molecular Study of Rare IVS-II-806 (G > C) (HBB:c.316-45G > C) Variant in the ß-globin Gene: A Possibly Benign Variant.

Introduction: ß-thalassemia is a common genetic disease affecting a single gene, disease with a high incidence in South China. We hereby, aim to provide the clinical and hematological features of a rare ß-globin gene variant in the Chinese population. Methods: Ten subjects from three unrelated Chinese families were enrolled in this study. Hematological analysis and thalassemia gene testing were preformed to screen for common α and ß-thalassemia variants. Gap-polymerase chain reaction (Gap-PCR) and DNA sequencing were utilized to examine the rare or novel thalassemia variants. Results: Six cases were identified carrying the rare IVS-II-806 (G > C) (HBB:c.316-45G > C) variant in the ß-globin gene. The proband in family 1 carry three rare ß-globin gene mutations including CD39 (C > T), IVS-II-81 (C > T) and IVS-II-806 (G > C) combined with a --SEA/αα deletion, exhibiting the ß-thalassemia trait. Further pedigree investigation indicated that the genotype of the proband in family 1 was --SEA/αα, ßCD39 (C>T), IVS-II-81(C>T)/ßIVS-II-806(G>C). Meanwhile, the twin girls in family 1 carrying the IVS-II-806 (G > C) mutation demonstrated a normal hematological phenotype. In family 2, the proband and his sister carry the IVS-II-806 (G > C) mutation, eliciting high levels of Hb A2 and slightly low levels of MCV and MCH. Moreover, the proband in family 3 carrying the same mutation exhibited a slightly low MCV level as well. Conclusions: In this study, clinical and hematological analysis of the IVS-II-806 (G > C) mutation was first conducted within the Chinese population, with results indicating that it may be a benign variant.

Third-Generation Sequencing as a New Comprehensive Technology for Identifying Rare α- and ß-Globin Gene Variants in Thalassemia Alleles in the Chinese Population.

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 α- and ß-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 α- and ß-globin gene variants. RESULTS.­: Twenty-three cases that carried rare variants in α- and ß-globin genes were identified by the routine detection methods. TGS technology yielded a 7.14% (5 of 70) increment of rare α- and ß-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 ß-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.

A de novo PAK1 likely pathogenic variant and a de novo terminal 1q microdeletion in a Chinese girl with global developmental delay, severe intellectual disability, and seizures.

BACKGROUND: Pathogenic PAK1 variants were described to be causative of neurodevelopmental disorder with macrocephaly, seizures, and speech delay. Herein, we present a de novo PAK1 variant combine with a de novo terminal 1q microdeletion in a Chinese pediatric patient, aiming to provide more insights into the underlying genotype-phenotype relationship. METHODS: Enrolled in this study was a 6-year-old girl with clinical features of global developmental delay, severe intellectual disability, speech delay, and seizures from Quanzhou region of China. Karyotype and chromosomal microarray analysis (CMA) were performed to detect chromosome abnormalities in this family. Whole exome sequencing (WES) was performed to investigate additional genetic variants in this family. RESULTS: No chromosomal abnormalities were elicited from the entire family by karyotype analysis. Further familial CMA results revealed that the patient had a de novo 2.7-Mb microdeletion (arr[GRCh37] 1q44(246,454,321_249,224,684) × 1]) in 1q44 region, which contains 14 OMIM genes, but did not overlap the reported smallest region of overlap (SRO) responsible for the clinical features in 1q43q44 deletion syndrome. In addition, WES result demonstrated a de novo NM_002576: c.251C > G (p.T84R) variant in PAK1 gene in the patient, which was interpreted as a likely pathogenic variant. CONCLUSION: In this study, we identify a novel PAK1 variant associated with a terminal 1q microdeletion in a patient with neurodevelopmental disorder. In addition, we believe that the main clinical features may ascribe to the pathogenic variant in PAK1 gene in the patient.

Etiological identification of recurrent male fatality due to a novel NSDHL gene mutation using trio whole-exome sequencing: A rare case report and literature review.

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.

[Genetic Analysis and Prenatal Diagnosis of Thalassemia in Couples of Childbearing Age in Quanzhou Region Fujian Province, China].

OBJECTIVE: To explore the genotypes and prenatal diagnosis of thalassemia in couples of childbearing age in Quanzhou, Fujian Province. METHODS: Blood routine and hemoglobin electrophoresis were performed for initial thalassemia screening in 76 328 couples in Quanzhou region from July 2017 to July 2020. The couples with positive initial screening results further underwent thalassemia gene test. Couples carrying homotypic thalassemia genes underwent prenatal diagnosis in the second trimester. RESULTS: Among 76 328 couples of childbearing age, 1 809 couples of positive initial thalassemia screening were identified, with the positive rate about 2.37%. Further results of genetic detection of the 1 809 couples showed that 985 cases were diagnosed as α- thalassemia, of which --sea/αα was the most frequency, followed by -α3.7/αα and ααQS/αα; 296 cases were diagnosed as ß-thalassemia, the most frequency mutations were 654M/N and 41-42M/N; 26 cases of compound α and ß-thalassemia were detected. In addition, 3 rare cases of thalassemia were detected, including --THAI/αα, SEA-HPFH, and -α6.9/--sea. Among them, 108 couples were confirmed as homologous thalassemia, with the detection rate about 5.97%, including 96 couples of homologous α-thalassemia, 9 couples of homologous ß-thalassemia, and 3 couples with one had compound α- and ß-thalassemia. Among them, 17 couples with homologous α-thalassemia underwent prenatal diagnosis in the second trimester, of which 1 case of Hb Bart's Hydrops Syndrome, 3 cases of HbH disease, 9 cases of silent thalassemia or α-thalassemia minor, and 4 cases of healthy fetuses were detected. Fetal chromosome karyotype analysis showed that 16 cases were normal and 1 case diagnosed as Down syndrome. CONCLUSION: Thalassemia screening in pre-marital and pre-pregnancy, and prenatal diagnosis can effectively reduce the birth of children with thalassemia intermediate and thalassemia major. It is necessary to perform chromosome karyotype analysis at the same time as prenatal diagnosis of thalassemia gene in order to avoid fetus with abnormal chromosome.

Molecular cytogenetic analysis of partial monosomy 10p and trisomy 10q resulting from familial pericentric inversion (10): a first case report in Chinese population.

BACKGROUND: Chromosome aberrations of 10p monosomy and 10q trisomy resulting from parental pericentric inversion 10 are extremely rare, and to date, very few reports have been published on the matter. CASE PRESENTATION: A 30-year-old pregnant woman with recurrent pregnancy loss is enrolled in this research. In this pregnancy, spontaneous abortion occurred in the first trimester of her pregnancy. Chromosomal microarray analysis of the abortion tissue showed a partial 10p monosomy (arr[GRCh37] 10p15.3p11.21(100,047_34,848,853) × 1) and a duplication of 10q (arr[GRCh37] 10q26.13q26.3(126,093,990_135,426,386) × 3). Further parental karyotype analysis indicated that the chromosomal abnormalities in the fetus was resulted from paternal pericenric inversion inv(10)(p11.21q26.13). This study presents the first case of a large deletion of 10p combined with 10q trisomy, resulting in pregnancy loss. Of these two manifestations, the large deletion of chromosome 10p may be the primary reason for spontaneous abortion in this subject. CONCLUSIONS: This study presents the first case of partial 10p monosomy associated with 10q trisomy in Chinese population. It provides more information on the chromosome aberration of 10p monosomy and 10q trisomy and further strengthens the application value of microarray in the molecular etiological diagnosis of recurrent spontaneous abortion.

Identification of a Rare Variant of c.1777G>A (p.G593S) in the COL1A1 Gene as the Etiology of Recurrent Osteogenesis Imperfecta by Whole-Exome Sequencing.

Background: Osteogenesis imperfecta (OI) is a rare heterogeneous disorder typically featured by fragile bones and susceptibility to fracture. The aim of the present study was to explore the genetic etiology of familial recurrent OI and the genotype-phenotype correlation. Methods: Karyotyping, chromosomal microarray analysis, and whole-exome sequencing (WES) were performed to determine the genetic etiology of OI in the enrolled family. Western blotting analysis was carried out using the fetal skin tissue for type I collagen production analysis. Results: At the first pregnancy, a c.1777G>A mutation in the COL1A1 gene was detected in the fetus who exhibited skeletal dysplasia. In this second pregnancy, severe fetal skeletal dysplasia was also presented without significant chromosomal abnormality detected by karyotype and chromosomal microarray analysis in the fetus. Further WES results demonstrated a de novo missense mutation of c.1777G>A (p.G593S) in the fetus, which was classified as a pathogenic variant according to the ACMG guidelines. The recurrent mutation in the two fetuses hinted at the possible existence of gonadal mosaicism in the parents, while no mutation in the COL1A1 gene was identified in the DNA from the father's sperm. In addition, Western blot results demonstrated no reduced type I procollagen production in the affected fetus compared with the age-matched controls. Conclusions: To the best of our knowledge, this is the first study that identified a rare variant of c.1777G>A in the COL1A1 gene that led to recurrent OI in the Chinese population. Additionally, we believe that this rare variant of c.1777G>A in the COL1A1 gene will lead to OI type II. The results of the present study further verify the application value of WES in identifying fetuses with ultrasound anomalies.

Case Report: Prenatal Whole-Exome Sequencing Identified a Novel Nonsense Mutation of the KCNH2 Gene in a Fetus With Familial 2q14.2 Duplication.

Background: Pathogenic mutations in the KCNH2 gene were associated with long QT syndrome 2 (LQT2), which typically manifest in a prolonged QT interval and may lead to recurrent syncopes, seizure, or sudden death. Limited reports indicated that the KCNH2 mutations would result in LQT2 combined with tetralogy of fallot. Our goal was to present an additional case of LQT2 combined with the tetralogy of fallot in a fetus with a novel KCNH2 mutation. Case presentation: Enrolled in this study was a 23-year-old pregnant woman from Quanzhou Fujian province, China. In her pregnancy, fetal ultrasound anomalies were identified, including tetralogy of fallot, coronary sinus enlargement, and persistent left superior vena cava. No chromosomal abnormality was detected by fetal karyotype analysis. However, 238.1-kb duplication in the 2q14.2 region containing the GLI2 gene was observed in the fetus by chromosomal array analysis, which was inherited from the mother with normal clinical features and interpreted as a variant of uncertain significance (VOUS). Furthermore, whole-exome sequencing (WES) detection identified a novel nonsense c.1907C > G (p.S636*) mutation in the KCNH2 gene in the fetus, and it was classified as a likely pathogenic variant, according to the ACMG guidelines. Parental verification analysis indicated that c.1907C > G (p.S636*) mutation was inherited from the mother. Conclusion: In this study, we believe that 2q14.2 duplication may not be the reason for fetal heart defects; moreover, we described an additional case with KCNH2 gene mutation, which may lead to LQTS and be associated with congenital heart defects. In addition, our study further confirms the application value of the WES technology in prenatal genetic etiology diagnosis of fetuses with structural anomalies and unexplained structural variants.