Parental origin of prenatally diagnosed pathogenic copy number variation in 56 pedigrees / 中华围产医学杂志

Objective:To investigate the prenatal management for pathogenic copy number variation (CNV) by analyzing the parental origin of CNV and pregnancy outcomes in 56 pedigrees.Methods:This study retrospectively analyzed the information of patients who received interventional prenatal diagnosis and chromosomal microarray analysis (CMA) at Guangzhou Women and Children's Medical Center from January 2015 to December 2020. The cases with pathogenic CNV indicated by CMA and receiving parental CMA for further verification were finally enrolled. Clinical data including prenatal diagnostic indications, chromosomal distribution of the pathogenic fragments and fragment sizes were collected and analyzed using t test. All cases were followed up by telephone and record review. Results:Fifty-six cases were included in this study. Pathogenic CNV in 13 (23.2%, 13/56) fetuses were inherited from one parent (eight from mothers and five from fathers), and mainly located in chromosomes 22 (3/13), 17 (3/11), 16 (2/7), 1 (2/4), and X (3/6) with fragment sizes all less than 3 Mb. The fragment size of inherited pathogenic CNV was significantly smaller than that of de novo CNV [1.69 (1.36-2.22) vs 7.54 (2.11-12.30) Mb, t=3.47, P=0.001]. Among the 43 cases with de novo pathogenic CNV, seven (16.3%) were lost to follow up and 35 (97.2%) terminated the pregnancy. The other one with a 0.58 Mb microruplication at 16p11.2 indicated at 37 gestational weeks gave birth to a baby weighting 2 900 g at 39 gestational weeks and no abnormalities were reported during an eight-month telephone follow-up. Two out of the 13 cases with inherited pathogenic CNV were lost to follow up and six pregnancies were terminated. The other five pregnancies were continued and babies were delivered with no abnormalities during a median follow-up period of 13 (4-15) months. Conclusion:Pathogenic CNV alone should not be the indication for pregnancy termination.

Genetic analysis and prenatal diagnosis of a fetus with Xq25 microduplication / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with structural brain abnormalities.@*METHODS@#The karyotypes of the fetus and its parents were analyzed by conventional G-banding. Chromosome microarray analysis (CMA) was carried out to detect chromosomal microdeletion and microduplication.@*RESULTS@#No kartotypic abnormality was detected in the fetus and its parents. CMA has identified a 194 kb microduplication at Xq25 in the fetus, which encompassed exons 4-35 of the STAG2 gene and was derived from its mother.@*CONCLUSION@#The Xq25 duplication encompassing part of the STAG2 gene probably underlay the brain malformation in the fetus.

Analysis of families with fetal congenital abnormalities but negative prenatal diagnosis by whole exome sequencing / 中华妇产科杂志

Objective:To evaluate the value of whole exome sequencing (WES) in prenatal clinical application.Methods:A total of 1 152 cases of congenital abnormal [including structural malformation, nuchal translucency (NT) thickening and intrauterine growth restriction] with traditional prenatal diagnosis [including G-band karyotype analysis and chromosome microarray analysis (CMA)] negative were analyzed. The congenital abnormal fetuses were divided into retrospective group and prospective group according to the time of WES detection, that is whether the pregnancy termination or not. According to the specific location of fetal malformation and their family history, the cohort was divided into subgroups. The clinical prognosis of all fetuses were followed up, and the effect of WES test results on pregnancy decision-making and clinical intervention were analyzed. According to the follow-up results, the data of fetuses with new phenotypes in the third trimester or after birth were re-analyzed.Results:Among 1 152 families who received WES, 5 families were excluded because of nonbiological parents. Among the remaining 1 147 families, 152 fetuses obtained positive diagnosis (13.3%,152/1 147), including 74 fetuses in the retrospective group (16.1%,74/460) and 78 fetuses in the prospective group (11.4%,78/687). In fetuses with negative CMA and G-band karyotype analysis results but new phenotypes in the third trimester or after birth, the positive rate by WES data re-analysis was 4.9% (8/163). A total of 34 (21.3%, 34/160) fetuses were directly affected by the corresponding positive molecular diagnosis. Among 68 cases of live births with diagnostic variation grade 4, 29 cases (42.7%, 29/68) received appropriate medical intervention through rapid review of WES results.Conclusions:WES could increase the detection rate of abnormal fetuses with negative G-banding karyotype analysis and CMA by 13.3%. Prenatal WES could guide pregnancy decision-making and early clinical intervention. It might be an effective strategy to pay attention to the special follow-up of the third trimester and postnatal fetus and to re-analyze the WES data.

Application of whole exome sequencing technology in fetuses with congenital structural abnormalities / 中华医学遗传学杂志

OBJECTIVE@#To investigate the application value of whole exome sequencing technology in fetuses with congenital structural abnormalities.@*METHODS@#The chromosomal abnormalities of 1147 families were analyzed. According to the follow-up results, the data of fetuses with new phenotypes in late pregnancy or after birth were reanalyzed. Subgroups were divided according to the organs involved and whether single malformation or not. The gene regulatory network map was drawn by using string database and Cytoscape software. Fisher exact probability method was used to compare the difference of the diagnostic rate of pathogenic genes among the groups.@*RESULTS@#A total of 160 fetal cases received positive molecular diagnosed, involving 178 variant sites of 125 pathogenic genes, including 8 cases (4.9%, 8/163) by data reanalysis, and the overall positive diagnosis rate was 13.9%. Diagnostic rate was highest in the group of skeletal malformation (31.5%, 39/124) and lowest in that with thoracic malformation (0, 0/32). The gene clusters of fetal edema and intrauterine growth restriction were independent, and were not associated with the major structural malformations. The probability of each parent carrying the same recessive gene variant was 0.03 (39/1146) and 0.08 (4/53) with positive family history.@*CONCLUSION@#For fetuses with congenital structural abnormalities that are negative for conventional genetic tests, 13.9% of phenotypic associated pathogenic/likely pathogenic genetic variants can be detected by whole exome sequencing technology. Its application value for prenatal diagnosis varies in fetus with different organs involved. Reanalysis of sequencing data for cases with new phenotypes in late pregnancy or after birth can further improve the molecular diagnosis rate. Further investigations are needed to explore the related genetic mechanisms.

Investigation and analysis of children's coal-burning-borne endemic fluorosis in Suojia Township, Liuzhi Tequ, Guizhou Province in 2019 / 中华地方病学杂志

Objective:To understand the current situation of children's fluorosis in the coal-burning-borne endemic fluorosis areas (abbreviated as coal-burning fluorosis) in Suojia Miao, Yi and Hui Township (Suojia Township for short) in Liuzhi Tequ, Guizhou Province, and to provide scientific basis for formulating prevention and control strategies and measures.Methods:In 2019, the cluster sampling method was adopted to select children aged 8-12 years old from 6 primary schools in Suojia Township, Liuzhi Tequ, Guizhou Province to conduct a questionnaire survey to collect basic information, and perform dental fluorosis examination and indexing in accordance with the "Diagnosis of Dental Fluorosis" standards. Immediate urine samples were collected from children in April and October, and urinary fluoride content was determined by ion selective electrode method.Results:A total of 1 381 children aged 8-12 years old were investigated, aged (9.84 ± 1.38) years old, including 679 boys and 702 girls. A total of 625 children with dental fluorosis were detected, and the detection rate was 45.26%; the dental fluorosis index was 1.00, and the prevalence intensity was moderate; the main score of dental fluorosis was extremely mild, accounting for 37.00% (511/1 381). The detection rates of dental fluorosis in children aged 8 to 12 years old were 35.10% (106/302), 35.83% (115/321), 47.96% (129/269), 55.23% (153/277), and 57.55% (122/212), respectively; the difference between different ages was statistically significant (χ 2 = 48.949, P < 0.01), and the detection rate of dental fluorosis in children increased with age(χ 2trend = 45.254, P < 0.01).The detection rates of dental fluorosis in boys and girls were 43.59% (296/679) and 46.87% (329/702), respectively, and there was no significant difference between different genders (χ 2 = 1.492, P > 0.05). In April and October, 123 and 107 urine samples of children aged 8-12 years old were tested. The geometric mean of urinary fluoride was 1.55 and 0.47 mg/L, respectively. The urinary fluoride level in April was higher than the normal range (< 1.40 mg/L). Conclusions:Suojia Township in Liuzhi Tequ of Guizhou Province is still a fluorosis area, and there is a big difference in urinary fluorine level in different months, which indicates that the residents in this area may have intermittent high fluorine intake, and prevention and control of endemic fluorosis should be further strengthened.

Clinical and molecular genetic analysis of a pediatric patient with Lowe syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology for a child with ocular dysplasia.@*METHODS@#Clinical examination was carried out. Medical history of the child was collected. Genomic DNA was extracted from peripheral blood samples. Chromosomal microarray analysis (CMA) was used to detect potential genomic copy number variations.@*RESULTS@#Ultrasonography revealed cataracts in both eyes of the child. MRI showed increased extracranial space, supratentorial ventricular dilatation, reduced white matter volume, increased T2WI signal and a large occipital cisterna. CMA showed that the patient carried a 249 kb microdeletion at Xq25q26.1 region, namely [hg19]arrXq25q26.1 (128 652 372 - 128 901 629)×0.@*CONCLUSION@#The child was diagnosed with Lowe syndrome, for which the 249 kb microdeletion at Xq25q26.1 is probably accountable.

Clinical and genetic analysis of three pediatric patients with 15q24 microdeletion syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for three patients with development delay and to correlate their clinical phenotypes with genetic findings.@*METHODS@#The karyotypes of the probands and their parents were analyzed by conventional G-banding. Chromosomal microarray analysis (CMA) was used to detect microdeletion and microduplication.@*RESULTS@#No kartotypic abnormality was detected in the patients and their parents. CMA analysis identified a de novo 3.10 Mb deletion on chromosome 15q24.1q24.2 in case 1, a de novo 3.14 Mb deletion at 15q24.1q24.2 in case 2, and a 3.13 Mb deletion at 15q24.1q24.2 in case 3. All deletions have encompassed the CPLX3,SEMA7A and SIN3A genes.@*CONCLUSION@#The three patients were diagnosed with 15q24 microdeletion syndrome. CPLX3,SEMA7A and SIN3A may be the key genes responsible for this syndrome.

Analysis of bone micro-CT results of patients with bone deformation exposed to high aluminum high fluoride / 中华地方病学杂志

Objective To analyze high alumina deformation Micro-CT findings of bone in patients with skeletal fluorosis in Shuicheng Guizhou Province.Methods Bone deformation children,youth and middle-aged patients with fluorosis in Goumi and Zhichang Townships Shuicheng County,coal-burning pollution endemic fluorosis areas,were selected as case group,and non-bone deformation children,youth,and children from non-fluorosis endemic areas as controls.Tibia and the anterior superior iliac spine tissue were obtained through orthopedic surgery and etiology examination,and resin embedded without decalcification.Resin-embedded bone tissue was scanned using micro-CT; relevant parameters were analyzed with ABA special bone analysis software INVEON Research Workplace and three dimensional reconstruction processing software Micview.Results ①The anterior superior iliac spine cancellous bone:compared between bone deformation children and bone non-deformation children in the diseased areas,there was an increasing tendency of the following items:relative volume of trabecular bone(0.337％ vs 0.229％),absolute thickness (μm:139 vs 133),quantities within a unit length (number/mm:2.44 vs 1.72),density woven degree of trabecular bone(number/mm:2.22 vs 1.54) and bone mineral density(mg/cm3:1 033 vs 918),while relative bone area of trabecular bone(mm2/mm3:14.5 vs 15.1) and space pitch (μm:0.274 vs 0.567) declined.Compared between bone deformation youth and bone non-deformation youth in the diseased areas,relative volume of trabecular bone was lower(0.217％ vs 0.437％),relative area increased (mm2/mm3:16.9 vs 11.6),absolute thickness reduced(μm:118 vs 172),trabecular number reduced (number/mm:1.83 vs 2.54),and space pitch increased (μm:0.427 vs 0.222),but density woven degree of trabecular bone increased (number/mm:4.61 vs 1.54),bone mineral density decreased(mg/cm3:977 vs 1 108),osteopenia,osteoporosis,bone mineral decreased,and an increase in the number of trabeculae crossing number.② Tibia bone tissue:compared between bone deformation children and bone non-deformation children in the diseased areas,relative volume of tibia trabecular bone increased(0.435％ vs 0.206％),relative volume of trabecular bone (mm2/mm3:12.3vs 12.4),and thickness (μm:188 vs 161) not changed obviously,trabecular number increased (number/mm:2.43 vs 1.28),space pitch reduced(μm:0.238 vs 0.621),density woven degree of trabecular bone decreased(number/mm:2.40 vs 3.48),bone mineral density increased(mg/cm3:1 047 vs 952),in general presented trabecular thickening,increased number and increased bone mineral.Compared between middle-aged patients with fluorosis in the diseased areas and children in non-fluorosis endemic areas,relative volume of trabecular bone (0.346％ vs 0.206％) and area (mm2/mm3:13.8 vs 12.4) increased,thickness of the trabecular bone reduced (μm:144 vs 161),trabecular number increased (number/mm:1.98 vs 1.28),space pitch decreased (μm:0.318 vs 0.621),and density woven degree of trabecular bone decreased (number/mm:2.60 vs 3.48).Conclusions The results of trabecular bone microstructure and bone mineral density have showed that the combined effects of aluminum and fluorine on human bone tissue at different developmental stages are different.High aluminum and fluorine load before the sexual development of children for trabecular bone thick dense,shows an increasing in bone mass and bone mineral deposition of bone sclerosis image.Bone deformation youth shows osteopenia osteoporosis and bone mineral deposition is reduced.Bone volume is slightly increased,the number of trabecular bone is increasing,trabecular structure is fine in middle-aged patients with skeletal fluorosis.