Copy number variation analysis and outcomes of 1 658 fetuses with increased nuchal translucency / 中华围产医学杂志

Objective:To analyze the genetic etiology and prognosis in fetuses with increased nuchal translucency (NT) in order to assist in the clinical prenatal genetic counseling and diagnosis.Methods:This study retrospectively enrolled 1 658 cases of singleton pregnancy (<35 years old) receiving invasive prenatal diagnosis, including karyotype analysis and/or chromosome microarray analysis or copy number variation (CNV) sequencing, due to NT value ≥2.5 mm in the first trimester in Henan Provincial People's Hospital from August 2014 to December 2021. They were divided into different groups according to the thickness of NT (≥2.5-<3.0, ≥3.0-<3.5, ≥3.5-<4.5, ≥4.5-<5.5, ≥5.5-<6.5 and ≥6.5 mm groups) and abnormal ultrasound findings (isolated increased NT group, increased NT complicated by soft markers/non-severe structural abnormality group and increased NT complicated by severe structural abnormality group). The results of invasive prenatal diagnosis and pregnancy outcomes were compared between different groups using Chi-square test and trend Chi-square test. Results:The detection rates of numerical abnormalities of chromosomes were 15.8% (262/1 658) and 17.6% (252/1 431) when the NT thickness cut-off value were 2.5 mm or 3.0 mm, respectively. Overall, the detection rate of numerical abnormalities of chromosomes increased with thickness of NT ( χ2trend=180.75, P<0.001), ranging from 6.6% (44/671) in the NT≥2.5-<3.5 mm group to 45.6% (113/248) in the NT≥5.5 mm group. The incidence of pathogenic/likely pathogenic CNV(P/LP CNV) did not increased with NT thickness ( χ2trend=3.26, P=0.071), and the highest detection rate was observed in the NT≥4.5-<5.5 mm group (9.0%, 19/211). The detection rate of numerical abnormalities of chromosomes plus P/LP CNV in the isolated NT≥2.5-<3.0 mm group and NT≥3.0-<3.5 mm group were 5.3% (10/188) and 9.6% (36/375), respectively, however, the difference was not statistically significant ( χ2=3.06, P=0.080). The detection rates of numerical abnormalities of chromosomes plus P/LP CNV in the isolated NT≥3.5-<4.5 mm group and NT≥2.5-<3.0 mm complicated by soft markers/ non-severe structural abnormality group were 12.7% (52/410) and 24.1% (7/29), respectively, and the risk were 2.6 times (95% CI: 1.3-5.2) and 5.7 times (95% CI: 2.0-16.4) of the isolated NT≥2.5-<3.0 mm group, respectively. The pregnancy termination rate increased with the NT thickness ( χ2trend=304.42, P<0.001), ranging from 10.8% (23/212) in the NT≥2.5-<3.0 mm group to 90.7% (117/129) in the NT≥6.5 mm group. After exclusion of the pregnancies terminated due to numerical abnormalities of chromosomes and P/LP CNV, 87.6% (862/984) of the fetus with increased NT were born alive. Conclusions:The detection rate of numerical abnormalities of chromosomes increases with the thickness of NT. Invasive prenatal diagnosis is required for non-advance aged singleton pregnant women when fetuses present with isolated NT≥2.5 mm with or without soft markers/structural abnormalities.

Early warning of low maternal unconjugated estriol level by prenatal screening for fetus with X-linked ichthyosis / 中华妇产科杂志

Objective:To analyze the characteristic of prenatal serological screening in fetus with X-linked ichthyosis (XLI), and to explore the relationship between unconjugated estriol (uE 3) levels and XLI. Methods:A total of 56 fetuses with Xp22.31 microdeletion indicated by prenatal diagnosis and 70 fetuses diagnosed with trisomy 21 and 26 fetuses with trisomy 18 in Henan Provincial People's Hospital and Affiliated Hospital of Weifang Medical College from September 2016 to June 2021 were collected. The multiples of median (MoM) values of uE 3, alpha-fetoprotein (AFP), and human chorionic gonadotropin (hCG) during the second trimester of pregnancy were retrospectively analyzed. Prenatal diagnosis was made by amniotic fluid karyotype analysis and genome copy number variant analysis, parent genetic verification and pathogenicity analysis were performed, and maternal and infant outcomes were followed up. Results:Of 56 pregnant women with fetal Xp22.31 microdeletion, 43 underwent serological screening during the second trimester of pregnancy, of which 42 were abnormal (39 male fetuses and 3 female fetuses). The median uE 3 MoM value of 39 male fetuses [0.06 (0.00-0.21)] was lower than the normal value and significantly lower than that of fetuses with trisomy 21 [0.71 (0.26-1.27)] and fetuses with trisomy 18 [0.36 (0.15-0.84)], the difference was statistically significant ( Z=99.96, P<0.001). While the MoM values of AFP and hCG were all within the normal range. Among the 56 fetuses carrying Xp22.31 microdeletion, 45 were male fetuses and 11 were female fetuses, and the deletion fragments all involved STS gene. Eighty-nine percent (50/56) were inherited from mother (49 cases) or father (1 case), and 11% (6/56) were de novo mutations. Follow-up showed 48 live births (38 males and 10 females) and 8 chose to terminate pregnancy (7 males and 1 female). Among the 38 male newborns, 37 presented with scaly skin changes from 1 to 3 months of age, and one had no clinical manifestations until 4 months after birth. Ten female newborns had no obvious clinical manifestations. Conclusions:The decrease levels of uE 3 MoM on maternal serological screening is closely related to the higher risk of XLI in male fetuses. For pregnant women with low uE 3 in serological screening or with family history of ichthyosis, in addition to chromosomal karyotype analysis, joint detection of genomic copy number variant analysis should be recommended.

Genetic analysis of 21 fetuses with high suspicion of congenital skeletal malformation by prenatal ultrasound / 中华围产医学杂志

Objective:To explore the genetic etiology of fetuses with high suspicion of congenital skeletal malformation detected by prenatal ultrasound.Methods:This retrospective study collected 21 pregnant women with highly suspected fetal skeletal malformation indicated by ultrasound (the couples had no skeletal malformation) at Institute of Medical Genetics, Henan Provincial People's Hospital from January 2019 to August 2020. Amniotic fluid/umbilical cord blood of the fetus and peripheral blood of the couples were obtained for karyotype analysis, chromosomal microarray analysis, and whole-exome sequencing. Sanger sequencing was performed for the "pathogenic" "suspected pathogenic" "variants of uncertain significance" variants detected by whole exome sequencing. Genetic etiology of the 21 fetuses was described.Results:A total of five chromosomal abnormalities were detected, including four cases of trisomy 21 and one trisomy 18. Chromosome microarray analysis detected one case of abnormal copy number variation, 16 p11.2 microdeletion syndrome. Ten cases of monogenic diseases were found by whole exome sequencing and eight genes were involved ( SGMS2, FGFR3, DYNC2H1, WDR35, TBX5, COL2A1, FGFR2, and ALPL). Totally, 14 variations were detected, among which seven were novel variations (c.8129T>A, c.7126G>A, c.10307_10320del, and c.2641G>T in DYNC2H1 gene; c.3085G>A and c.491G>A in WDR35 gene; c.1070G>T in COL2A1 gene). Conclusions:For fetus, whose parents have no skeletal malformation, highly suspected of congenital malformation of skeletal system by prenatal ultrasound, genetic factor is the primary reason, including chromosomal abnormalities, copy number variations, and monogenic mutations.

Identification and analysis of anovel variant of TRAPPC2 in a X-linked spondyloepiphyseal dysplasia tarda pedigree / 中华骨科杂志

Objective:To provide experimental evidence for genetic counseling and prenatal diagnosis by analyzing the clinical characteristics, screening and identification of the function of suspicious variants in a X-1inked spondyloepiphyseal dysplasia tarda (SEDT) family.Methods:The family members' medical history, general physical examination, femur, spine X-ray examination were collected. Peripheral blood samples of the family members were collected and DNA was extracted from these samples. Sequencing clinical whole exons of proband DNA by targeted gene high-throughput sequencing method, then analysis sequencing data. The suspicious mutation was confirmed in pedigree members by PCR and Sanger sequencing. Reverse transcription polymerase chain reaction (RT-PCR) experiments of total RNA from blood lymphocytes were performed. The amplification of exons 3 and 4 of the pathogenic gene were amplified and identified by agarose gel. The expression of the pathogenic gene was also detected.Results:Three affected males of the family were diagnosed with SEDT according to their clinical and radiological features. A nonsense mutation in the transport protein particle complex subunit 2 ( TRAPPC2) gene NM_001011658: c.91A>T (p.K31*) was found in the proband using whole exome sequencing. This variation was also detected in his cousin, but not in non-phenotypic members of the family. The RT-PCR result for amplification of exon 3 and 4 of peripheral blood lymphocytes was the same as those of normal controls, indicating that the mutation did not affect the splicing of transcripts. qPCR results showed that the transcriptional expression of TRAPPC2 in patients was significantly lower than that in family normal controls and normal people controls. Conclusion:Identification of the novel nonsense mutation (c.91A>T) in the SEDT family enables early patients screening, carrier detection, genetic counseling, prenatal diagnosis, and clinical prevention and treatment. The detailed genotype/phenotype descriptions contribute to the SEDT mutation spectrum. The study of the function of TRAPPC2 mutation will help to further elucidate the role of sedlin in cartilage.

Application of genomic copy number variation detection technology in prenatal diagnosis of 7617 pregnant women with serological screening abnormalities during the second trimester of pregnancy / 中华医学遗传学杂志

OBJECTIVE@#To analyze the genomic variation characteristics of fetal with abnormal serological screening, and to further explore the value of copy number variation (CNV) detection technology in prenatal diagnosis of fetal with abnormal serological screening.@*METHODS@#7617 singleton pregnant women who underwent amniocentesis for prenatal diagnosis solely due to abnormal Down's serological screening were selected. According to the results of serological screening, the patients were divided into high risk group, borderline risk group and single abnormal multiple of median (MOM) group. CMA and CNV-Seq were used to detect the copy number variation of amniotic fluid cell genomic DNA and combined with amniotic fluid cell karyotype analysis for prenatal diagnosis. Outpatient revisit combined with telephone inquiry was used for postnatal follow-up.@*RESULTS@#Among 7617 amniotic fluid samples, aneuploidy was detected in 138cases (1.81%) by CMA and CNV-Seq, 9 cases of aneuploid chimerism were detected by amniotic fluid cell karyotype analysis, and 203 cases of fetus carrying pathogenic and likely pathogenic CNV (P/LP CNV) were detected, the variant of uncertain significance (VUS) was detected in 437 cases (5.7%), the overall abnormal detection rate was 10.33%. The detection rate of aneuploidy by CMA and CNV-Seq in three group were 123 cases (2.9%), 13 cases (1.3%) and 2 cases (0.4%), respectively,and showing no significant difference (χ 2=7.469, P=0.024). The detection rate of pathogenic and likely pathogenic CNV in three group were 163cases (2.6%); 24 cases (2.6%) and 16 cases (3.3%), respectively, and showing no significant difference (χ 2=0.764, P=0.682). The CMA reported 2.9% (108/3729)P/LP CNV, and CNV-seq reported 2.4% (95/3888)P/LP CNV, both tests showed similar detective capabilities (χ 2=1.504, P=0.22).The most popular P/LP CNV in this cohort were Xp22.31 microdeletion, 16p13.11 microduplication /microdeletion, 22q11.21 microduplication /microdeletion. In fetuses with P/LP CNV CNV, 59 fetuses were terminated pregnancy, and 32 of 112 fetuses born had abnormal clinical manifestations. Non-medically necessary termination of pregnancy occurred in 11 fetuses carrying VUS CNV, 322 fetuses carrying VUS CNV were born, 4 of them presented abnormal clinical manifestations.@*CONCLUSION@#Compared with the traditional chromosome karyotype, CMA and CNV-Seq can improve the detection rate of pathogenic and likely pathogenic CNV. CMA and CNV-seq can be used for first tier diagnosis of pregnant women in the general population with abnormal Down's serological screening.

Genetic analysis and prenatal diagnosis of a Chinese pedigree affected with Usher syndrome due to novel compound heterozygous variants of PCDH15 gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical features and genetic variant in a patient with Usher syndrome.@*METHODS@#Whole exome sequencing was carried out for the patient. Suspected variants were validated by Sanger sequencing of her parents and fetus.@*RESULTS@#The proband was found to harbor compound heterozygous variants c.17_18insA (p.Tyr6Ter*) and c.4095_4096insA (p.Arg1366Lys fs*38) of the PCDH15 gene (NM_033056), which were respectively inherited from her father and mother. The same variants were not detected in 100 healthy controls. Based on the guidelines of the American Society of Medical Genetics and Genomics, both variants were predicted to be pathogenic (PVS1+PM2+PP4). By prenatal diagnosis, her fetus was found to carry the c.4095_4096insA variant. After birth, the child has passed neonatal hearing screening test, and no abnormal auditory and visual function was found after the first year.@*CONCLUSION@#The compound heterozygous variants c.17_18insA (p.Tyr6Ter*) and c.4095_4096insA (p.Arg1366Lys fs*38) of the PCDH15 gene probably underlay the Usher syndrome is this proband.

Analysis of a Chinese pedigree affected with dyschromatosis symmetrica hereditaria due to a novel variant of ADAR gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with dyschromatosis symmetrica hereditaria (DSH).@*METHODS@#PCR and Sanger sequencing were carried out for the proband, and suspected variant was validated by Sanger sequencing in the pedigree.@*RESULTS@#The proband was found to harbor a novel variant of c.1352delA (p.N451Mfs*13) of the ADAR (NM_001111) gene. The same variant was found in her affected mother and sister, but not in her unaffected father, uncle, and 100 healthy individual.@*CONCLUSION@#The novel variant of the ADAR gene probably underlay the pathogenesis of DSH in this pedigree.

Genotypic and phenotypic analysis of RHO gene variants in a Chinese Han autosomal dominant retinitis pigmentosa family / 中华实验眼科杂志

Objective:To analyze the pathogenic genes and clinical phenotypes of a Chinese Han family with autosomal dominant retinitis pigmentosa (ADRP).Methods:A pedigree investigation study was conducted, and a Chinese Han RP family that underwent genetic counseling in the Henan Provincial People's Hospital in November 2019 was collected.Twenty members of this family from 4 generations, including 9 patients and 11 phenotypically normal individuals, were enrolled.Visual acuity, peripheral visual field test and fundus examination were performed on some family members.Peripheral blood samples were collected from the family members, and DNA was extracted.Exon-targeted sequencing containing 43 genes associated with RP was performed on the proband using the Ion Torrent PGM sequencing platform.The mutations were verified by polymerase chain reaction and Sanger sequencing.Online software was applied to predict the protein function of the variant.The amino acid sequences of the variant loci were compared using the ClustalW2 multiplex alignment program.The pathogenicity of the variant was analyzed according to American College of Medical Genetics and Genomics (ACMG) criteria and guidelines for classification of genetic variant.This study adhered to the Declaration of Helsinki.The study protocol was approved by an Ethics Committee of Henan Provincial People's Hospital (No.HNEECKY-2019[15]).Results:The family was consistent with autosomal dominant inheritance.The proband, a 26-year-old male, had bilateral night blindness since childhood, with visual acuity of 0.25 in the right eye and 0.5 in the left eye.There was osteoblast-like pigmentation in his both retinas, thinned retinal vessels and pale optic disc.Full-field electroretinogram examination showed reduced scotopic a- and b-wave peaks and severely reduced photopic a- and b-wave peaks.The rest of the family began to develop night blindness when 7 to 10 years old, having complete loss of peripheral vision around 50 years of age, and typical RP changes were found in ophthalmic examination.Genetic testing revealed a heterozygous missense variant c. 982delC (p.L328fs) in exon 5 of the family's rhodopsin ( RHO) gene (NM_000539.3). This variant resulted in the change of 21 amino acids after amino acid 328 in the encoded RHO protein, increasing amino acids in the coding region from 348 to 358 and altering the structure of the RHO protein.The analysis of protein homology sequence alignment between several different species showed that the locus was highly conserved.According to the guidelines of the ACMG criteria and guidelines for classification of genetic variants, the variant was a pathogenic mutation because there were six evidences including one very strong evidence of pathogenicity PVS1, two moderate evidences of pathogenicity PM2 and three supporting evidences of pathogenicity, PP1, PP3 and PP4. Conclusions:The c. 982delC variant in the RHO gene is a pathogenic mutation in this pedigree, and this variant is reported for the first time in a Chinese Han family.

Clinical characteristics and pathogenic gene analysis in a large pedigree with multiple epiphyseal dysplasia / 中华骨科杂志

Objective@#To provide experimental evidence for genetic counseling and prenatal molecular diagnosis by analyzing the clinical characteristics and screening for pathogenic genes of a five-generation suspected multiple epiphyseal dysplasia (MED) family (17 patients).@*Methods@#The family members' medical history, general physical examination and hip joint X-ray examination were collected. Peripheral blood samples of the family members were collected and DNA were extracted from these samples. The exons of clinical genes from probands' DNA were sequenced by High throughput sequencing method. Next Gene software was used to compare and analyze the sequence and INGENUITY software was further used to annotate the mutations in order to find the pathogenic mutations in probands. The suspicious mutations were confirmed in pedigree members by PCR and Sanger sequencing.@*Results@#The family consisted of 5 generations and 38 members. Pedigree analysis was consistent with autosomal dominant inheritance. There were 17 patients in the family, and their clinical manifestations showed abnormal walking posture in childhood, pain in hip and knee joints, and typical pathological changes of epiphyseal dysplasia on X-ray. Cartilage oligomeric matrix protein (COMP) gene c.1153G>A (p.Asp385Asn) missense heterozygous mutation was screened in proband, which was genotypically and phenotypically segregated in the pedigree.@*Conclusion@#A missense mutation of the comp gene has been identified in a pedigree affected with MED which was the first reported in a big family. Our result is conducive to the further diagnosis and treatment and also provides a molecular basisfor the future prenatal diagnosis.

Genetic analysis of a patient with late infantile metachromatic leukodystrophy / 中华医学遗传学杂志

OBJECTIVE@#To detect variants of ARSA gene in a child featuring late infantile metachromatic leukodystrophy (MLD).@*METHODS@#PCR and Sanger sequencing was carried out for the patient and her parents.@*RESULTS@#The patient had typical features of MLD including ARSA deficiency, regression of walking ability, and demyelination. Compound heterozygous variants of the ARSA gene, namely c.960G>A and c.244C>T, were detected in the patient, for which her mother and father were respectively heterozygous carriers. ARSA c.960G>A was known to be pathogenic, while ARSA c.244C>T was a novel variant. The same variants were not detected among 50 healthy controls.@*CONCLUSION@#The compound heterozygous variants c.960G>A and c.244C>T of the ARSA gene probably underlie the MLD in this patient.

Identification of SPAST gene variant in a pedigree affected with hereditary spastic paraplegia type 4 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pedigree affected with hereditary spastic paraplegia type 4 (HSP4).@*METHODS@#Peripheral venous blood samples were taken from members of the four-generation pedigree and 50 healthy controls for the extraction of genomic DNA. Genes associated with peripheral neuropathy and hereditary spastic paraplegia were captured and subjected to targeted capture and next-generation sequencing. The results were confirmed by Sanger sequencing.@*RESULTS@#DNA sequencing suggested that the proband has carried a heterozygous c.1196C>G variant in exon 9 of the SPAST gene, which can cause substitution of serine by threonine at position 399 (p.Ser399Trp) and lead to change in the protein function. The same variant was also detected in other patients from the pedigree but not among unaffected individuals or the 50 healthy controls. Based on the ACMG 2015 guidelines, the variant was predicted to be possibly pathogenic.@*CONCLUSION@#The c.1196C>G variant of the SPAST gene probably underlay the HSP4 in this pedigree.

A case of hyaline fibromatosis syndrome caused by compound heterozygous mutations in the ANTXR2 gene / 中华皮肤科杂志

A female patient aged 7 years and 5 months presented with multiple skin defects of the scalp, ears, hands and in the sacrococcygeal region, and multiple joint flexion contractures of the extremities for more than 7 years. Skin examination showed skin defects of the scalp, auricles, hands and in the sacrococcygeal region, gingival swelling, and multiple joint flexion contractures of the extremities. Genetic testing of the peripheral blood revealed 2 compound heterozygous mutations c.1073delC (A359Lfs*51) and c.1073dupC (A359Cfs*13) in the anthrax toxin receptor-2 ( ANTXR2) gene in the patient, which were inherited from her mother and father respectively. The patient was diagnosed with hyaline fibromatosis syndrome. Surgical treatment was rejected, and anti-inflammatory drugs, analgesics and other drugs were administered for symptomatic treatment. During follow-up of half a year, the child occasionally had mild diarrhea, and other symptoms did not progress markedly.

Clinical characteristics and pathogenic gene analysis in a large pedigree with multiple epiphyseal dysplasia / 中华骨科杂志

Objective To provide experimental evidence for genetic counseling and prenatal molecular diagnosis by analyzing the clinical characteristics and screening for pathogenic genes of a five-generation suspected multiple epiphyseal dysplasia (MED) family (17 patients).Methods The family members' medical history,general physical examination and hip joint X-ray examination were collected.Peripheral blood samples of the family members were collected and DNA were extracted from these samples.The exons of clinical genes from probands' DNA were sequenced by High throughput sequencing method.Next Gene software was used to compare and analyze the sequence and INGENUITY software was further used to annotate the mutations in order to find the pathogenic mutations in probands.The suspicious mutations were confirmed in pedigree members by PCR and Sanger sequencing.Results The family consisted of 5 generations and 38 members.Pedigree analysis was consistent with autosomal dominant inheritance.There were 17 patients in the family,and their clinical manifestations showed abnormal walking posture in childhood,pain in hip and knee joints,and typical pathological changes of epiphyseal dysplasia on X-ray.Cartilage oligomeric matrix protein (COMP) gene c.1153G ＞ A (p.Asp385Asn) missense heterozygous mutation was screened in proband,which was genotypically and phenotypically segregated in the pedigree.Conclusion A missense mutation of the comp gene has been identified in a pedigree affected with MED which was the first reported in a big family.Our result is conducive to the further diagnosis and treatment and also provides a molecular basisfor the future prenatal diagnosis.

Prenatal diagnosis of a fetus affected with Finnish type congenital nephrotic syndrome / 中华医学遗传学杂志

Objective@#To explore the genetic basis for a fetus suspected for congenital nephrotic syndrome of Finland (CNF).@*Methods@#Genomic DNA was extracted from peripheral and umbilical cord blood samples derived from both parents and the fetus. Potential variants were detected by using next-generation sequencing. Suspected variants were confirmed by Sanger sequencing.@*Results@#The fetus was found to carry compound heterozygous variants c. 1440+ 1G>A and c. 925G>T of the NPHS1 gene, which were respectively inherited from its mother and father.@*Conclusion@#Identification of the compound heterozygous NPHS1 variants has enabled diagnosis of CNF in the fetus and genetic counseling for the affected family.

Identification of two novel Parkin gene mutations in a patient affected with Juvenile Parkinson's syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic features of a patient suspected with Juvenile Parkinson's syndrome (JP).@*METHODS@#Clinical features of the patient were analyzed. Genomic DNA of the patient and his parents was extracted from peripheral blood samples and sequenced by exome capture sequencing. The nature and impact of detected mutations were predicted and validated.@*RESULTS@#The patient displayed typical features including resting tremor, bradykinesia, rigidity, but with excellent response to low dose levodopa. DNA sequencing showed that she has carried compound heterozygous mutations of the Parkin gene, namely c.1381dupC and c.619-1G>C, which were respectively inherited from his mother and father. Neither mutation was reported previously. Bioinformatic analysis predicted that both mutations are pathogenic.@*CONCLUSION@#The patient has JP caused by mutations of the Parkin gene. Exome capture sequencing is an accurate and efficient method for genetic diagnosis of such disease.

A novel compound heterozygous mutation of GNPTAB gene underlying a case with mucolipidosis type II α/β / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical features and genetic mutations in a patient with mucolipidosis type II α/β by using next generation sequencing.@*METHODS@#Clinical data of the patient was collected. Genomic DNA of the patient and her parents was extracted by a standard method. The patient was subjected to targeted sequencing using an Ion Ampliseq panel, which included genes related to mucolipidosis and mucopolysaccharidosis. Suspected mutations were verified by Sanger sequencing.@*RESULTS@#Compound heterozygous mutations, namely c.1284+1G>T and c.1090C>T (p.Arg364*), were detected in the patient, which were respectively inherited from her mother and father. No other disease-causing mutation was detected in the patient. GNPTAB c.1090C>T was known to be pathogenic, while GNPTAB c.1284+1G>T is a novel mutation. The same mutations were not detected among 50 healthy controls.@*CONCLUSION@#The compound heterozygous mutations c.1284+1G>T and c.1090C>T (p.Arg364*) of GNPTAB gene probably account for the mucolipidosis type II α/β in the patient. NGS has a great value for the molecular diagnosis and typing of mucolipidosis.

Genetic analysis of a pedigree affected with Bartter's syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pedigree affected with Bartter's syndrome (BS).@*METHODS@#Panel-based next-generation sequencing (NGS) was carried out to detect mutation in BS-related genes SLC12A1, KCNJ1, BSND and CLCNKB. Sanger sequencing of MAGED2 gene and chromosomal microarray analysis (CMA) were also performed on the patient. Suspected mutation was validated in her family members.@*RESULTS@#No pathogenic mutation was detected by NGS, while a 0.152 Mb microdeletion at Xp11.21 (54 834 585-54 986 301) was found in the male fetus, which removed the entire coding region of the MAGED2 gene. His mother was a heterozygous carrier of the deletion. His father and sister did not carry the same deletion.@*CONCLUSION@#The loss of the MAGED2 gene may underlie the BS in this pedigree.

Prenatal diagnosis of partial trisomy 3q in a fetus / 中华医学遗传学杂志

OBJECTIVE@#To carry out prenatal diagnosis for a fetus with ultrasonographic abnormality.@*METHODS@#Chromosomal karyotyping and array comparative genomic hybridization (array-CGH) analysis were applied for the diagnosis. Peripheral blood samples were also taken from the parents for chromosome karyotyping analysis.@*RESULTS@#The fetal karyotype showed additional material of unknown-origin attached to Yq. Array CGH analysis confirmed that the material was derived from 3q22.1q29. The father was found to carry a balanced translocation 46, X, t(Y;3)(q12;q23) (which was diagnosed as 46,XY,Y≥18 elsewhere), whilst the mother was found to be normal.@*CONCLUSION@#3q partial trisomy may present as malformation of multiple systems. Combination of chromosome karyotyping and array-CGH can provide reliable diagnosis for fetuses with abnormalities by ultrasonography.

Prenatal diagnosis of a fetus affected with Finnish type congenital nephrotic syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus suspected for congenital nephrotic syndrome of Finland (CNF).@*METHODS@#Genomic DNA was extracted from peripheral and umbilical cord blood samples derived from both parents and the fetus. Potential variants were detected by using next-generation sequencing. Suspected variants were confirmed by Sanger sequencing.@*RESULTS@#The fetus was found to carry compound heterozygous variants c.1440+1G>A and c.925G>T of the NPHS1 gene, which were respectively inherited from its mother and father.@*CONCLUSION@#Identification of the compound heterozygous NPHS1 variants has enabled diagnosis of CNF in the fetus and genetic counseling for the affected family.

Analysis of WAS gene mutation in a Chinese family affected with Wiskott-Aldrich syndrome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect potential mutation of the WAS gene in a Chinese family affected with Wiskott-Aldrich syndrome.</p><p><b>METHODS</b>Peripheral blood samples were collected from the proband and his family members. All exons and flanking regions of the WAS gene were subjected to PCR amplification - Sanger sequencing as well as restriction endonuclease analysis. Plasma level of B-cell activating factor (BAFF) was also determined for all family members.</p><p><b>RESULTS</b>A hemizygous mutation (c.257G>A) of the WAS gene was identified in all patients from the family, for which the patient's mother was heterozygous. The same mutation was not found among healthy members of the family. Compared with unaffected members, all patients had a higher level of BAFF.</p><p><b>CONCLUSION</b>The c.257G>A mutation of the WAS gene probably underlies the Wiskott-Aldrich syndrome in this family.</p>