Chromosomal Microarray Analysis Research Articles

Lack of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile-onset brainstem neurodegenerative disease with early lethality

BackgroundCongenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among them, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Biallelic pathogenic variants in NDUFAF2, encoding the nuclear assembly CI factor NDUFAF2, were initially reported to cause progressive encephalopathy beginning in infancy. Since the initial report in 2005, less than a dozen patients with NDUFAF2-related disease have been reported.MethodsClinical, biochemical, and neuroradiological features of four new patients residing in Northern Israel were collected during 2016–2022 at Emek Medical Center. Enzymatic activities of the five respiratory-chain complexes were determined in isolated fibroblast mitochondria by spectrophotometric methods. Western blot analyses were conducted with anti-human NDUFAF2 antibody; antibody against the mitochondrial marker VDAC1 was used as a loading control. Genetic studies were performed by chromosome microarray analysis using Affymetrix CytoScan 750 K arrays.ResultsAll four patients presented with infantile-onset growth retardation, ophthalmological impairments with nystagmus, strabismus (starting between 5 and 9 months), and further progressed to life-threatening episodes of apnea usually triggered by trivial febrile illnesses (between 10 and 18 months) with gradual loss of acquired developmental milestones (3 of 4 patients). Serial magnetic-resonance imaging studies in two of the four patients showed a progressive pattern of abnormal T2-weighted hyperintense signals involving primarily the brainstem, the upper cervical cord, and later, the basal ganglia and thalami. Magnetic-resonance spectroscopy in one patient showed an increased lactate peak. Disease progression was marked by ventilatory dependency and early lethality. 3 of the 4 patients tested, harbored a homozygous 142-kb partial interstitial deletion that omits exons 2–4 of NDUFAF2. Mitochondrial CI activity was significantly decreased in the only patient tested. Western blot analysis disclosed the absence of NDUFAF2 protein compared to normal controls. In addition, we reviewed all 10 previously reported NDUFAF2-deficient cases to better characterize the disease.ConclusionsBiallelic loss-of-function mutations in NDUFAF2 result in a distinctive phenotype in the spectrum of Leigh syndrome with clinical and neuroradiological features that are primarily attributed to progressive brainstem damage.

The application of the ICD-10 for antepartum stillbirth patients in a referral centre of Eastern China: a retrospective study from 2015 to 2022

BackgroundThe causes of some stillbirths are unclear, and additional work must be done to investigate the risk factors for stillbirths.ObjectiveTo apply the International Classification of Disease-10 (ICD-10) for antepartum stillbirth at a referral center in eastern China.MethodsAntepartum stillbirths were grouped according to the cause of death according to the International Classification of Disease-10 (ICD-10) criteria. The main maternal condition at the time of antepartum stillbirth was assigned to each patient.ResultsAntepartum stillbirths were mostly classified as fetal deaths of unspecified cause, antepartum hypoxia. Although more than half of the mothers were without an identified condition at the time of the antepartum stillbirth, where there was a maternal condition associated with perinatal death, maternal medical and surgical conditions and maternal complications during pregnancy were most common. Of all the stillbirths, 51.2% occurred between 28 and 37 weeks of gestation, the main causes of stillbirth at different gestational ages also differed. Autopsy and chromosomal microarray analysis (CMA) were recommended in all stillbirths, but only 3.6% received autopsy and 10.5% underwent chromosomal microarray analysis.ConclusionsThe ICD-10 is helpful in classifying the causes of stillbirths, but more than half of the stillbirths in our study were unexplained; therefore, additional work must be done. And the ICD-10 score may need to be improved, such as by classifying stillbirths according to gestational age. Autopsy and CMA could help determine the cause of stillbirth, but the acceptance of these methods is currently low.

Polyhydramnios associated with rare genetic syndromes: two case reports

BackgroundWe present two genetic causes of polyhydramnios that were challenging to diagnose due to their rarity and complexity. In view of the severe implications, we wish to highlight these rare genetic conditions when obstetricians consider differential diagnoses of polyhydramnios in the third trimester.Case presentationPatient 1 is a 34-year-old Asian woman who was diagnosed with polyhydramnios at 28 weeks’ gestation. First trimester testing, fetal anomaly scan, and intrauterine infection screen were normal. Subsequent antenatal ultrasound scans revealed macroglossia, raising the suspicion for Beckwith–Wiedemann syndrome. Chromosomal microarray analysis revealed a female profile with no pathological copy number variants. The patient underwent amnioreduction twice in the pregnancy. The patient presented in preterm labor at 34 weeks’ gestation but elected for an emergency caesarean section. Postnatally, the baby was noted to have a bell-shaped thorax, coat hanger ribs, hypotonia, abdominal distension, and facial dysmorphisms suggestive of Kagami–Ogata syndrome. Patient 2 is a 30-year-old Asian woman who was diagnosed with polyhydramnios at 30 weeks’ gestation. She had a high-risk first trimester screen but declined invasive testing; non-invasive prenatal testing was low risk. Ultrasound examination revealed a macrosomic fetus with grade 1 echogenic bowels but no other abnormalities. Intrauterine infection screen was negative, and there was no sonographic evidence of fetal anemia. She had spontaneous rupture of membranes at 37 + 3 weeks but subsequently delivered by caesarean section in view of pathological cardiotocography. The baby was noted to have inspiratory stridor, hypotonia, low-set ears, and bilateral toe polysyndactyly. Further genetic testing revealed a female profile with a pathogenic variant of the GLI3 gene, confirming a diagnosis of Greig cephalopolysyndactyly syndrome.ConclusionThese cases illustrate the importance of considering rare genetic causes of polyhydramnios in the differential diagnosis, particularly when fetal anomalies are not apparent at the 20-week structural scan. We would like to raise awareness for these rare conditions, as a high index of suspicion enables appropriate counseling, prenatal testing, and timely referral to pediatricians and geneticists. Early identification and diagnosis allow planning of perinatal care and birth in a tertiary center managed by a multidisciplinary team.

Chondrolipoma of the Breast: A Myofibroblastoma Variant or a Distinct Lesion?

The entity commonly referred to as chondrolipoma is a rare and enigmatic breast lesion with unclear histogenesis and a complete lack of molecular characterization. It is uncertain whether it represents a hamartoma, choristoma, or a distinct neoplasm, including possibly a variant of mammary-type myofibroblastoma. We report two additional chondrolipomatous lesions of the breast. The lesions had varying histologic and immunohistochemical features similar to myofibroblastoma, including the loss of retinoblastoma (Rb) protein expression in one lesion. Molecular analysis by chromosomal microarray analysis performed on a second lesion did not demonstrate a loss of 13q14 or 16q typical of myofibroblastoma. Our findings further support the concept that at least a subset of breast lesions that historically have been classified as chondrolipoma are related to myofibroblastoma. However, the lack of myofibroblastoma-specific molecular alterations in one lesion suggests chondrolipomas may also have varying origins.

Genetic analysis of a fetus with Meckel syndrome due to variants of TMEM67 gene

To carry out prenatal diagnosis for a fetus with Meckel syndrome (MKS) and explore its genetic basis. A pregnant woman presented at Suzhou Municipal Hospital in February 2018 was selected as the study subject. Clinical data was collected. Muscle tissue sample from the abortus and peripheral blood samples from the couple were collected. Genomic DNA was extracted and subjected to chromosomal microarray analysis (CMA) and whole exome sequencing. Candidate variant was verified by Sanger sequencing. The fetus was found to have microcephaly, oligohydramnios, polycystic kidneys and banana-shaped cerebellum at 18 weeks of gestation. After induction of labor, it was found to have encephalocele, renal cysts and polydactyly. CMA has found no abnormality. Whole exome sequencing revealed novel compound heterozygous variants c.296delA (p.Lys99SerfsTer6) and c.1243G>A (p.Val415Met) in the TMEM67 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.296delA variant was predicted to be pathogenic (PVS1+PM2_Supporting+PP4), whilst the c.1243G>A variant was predicted to be likely pathogenic (PM2_Supporting+PM3+PP3_Moderate+PP4). The c.296delA and c.1243G>A compound heterozygous variants of the TMEM67 gene probably underlay the MKS in this fetus.

Genetic diagnosis and analysis of eight cases with central 22q11.2 deletion syndrome

To explore the pregnancy outcome and postpartum clinical phenotype of LCR22B/C~D central 22q11.2 deletion syndrome. For fetuses diagnosed with central 22q11.2 deletion by chromosomal microarray analysis (CMA) at the Prenatal Diagnosis Center of the Third Affiliated Hospital of Zhengzhou University from January 2019 to April 2022, their prenatal imaging, parental CMA verification, pregnancy outcomes and postpartum clinical phenotype were analyzed. Eight cases of central 22q11.2 deletion syndrome were included, including six cases with LCR22B~D 22q11.2 deletions and two with LCR22C~D 22q11.2 deletions. Among the six cases with LCR22B~D type 22q11.2 deletions, three had shown cardiovascular malformations (right aortic arch, ventricular septal defect, mild tricuspid regurgitation), one had shown urinary defect (right kidney heterotopia). Two cases with LCR22C~D 22q11.2 deletions showed nonspecific ultrasonographic findings, including oligohydramnios with growth restriction and nuchal skin thickening. The CMA verification showed that six cases were inherited from their parents, and five couples had chosen to continue with the pregnancy. Postpartum follow-up showed that the physical and intellectual development of all children were normal. One couple had opted to terminate the pregnancy considering the ectopic fetal right kidney. Two remaining cases had decided to terminate their pregnancies without parental verification. The central 22q11.2 deletion syndrome of the LCR22B/C~D type is different from the classical types. Its genetic information mainly comes from parents. Prenatal imaging has mainly shown cardiovascular and urinary abnormalities. Postnatal growth and intellectual development have been normal. Therefore, the couples should be provided with suffice prenatal genetic counseling.

Expanding the Role of Chromosomal Microarray Analysis in the Evaluation of Recurrent Pregnancy Loss

Multiple factors contribute to recurrent pregnancy loss (RPL). This review highlights the latest international guidelines for RPL workup, including immunological testing, by the American Society for Reproductive Medicine (ASRM), the European Society of Human Reproduction and Embryology (ESHRE), and the Royal College of Obstetricians and Gynaecologists (RCOG). These three societies recommend testing for antiphospholipid syndrome. ESHRE and RCOG also recommend thyroid peroxidase antibody testing, whereas ASRM does not. All guidelines advise against testing of natural killer cells, cytokines, antinuclear antibodies, human leukocyte antigen (HLA) compatibility, anti-HLA antibodies, and anti-sperm antibodies. However, when following ASRM, ESHRE or RCOG diagnostic guidelines, over 50% of cases have no identifiable cause. Genetic testing of products of conception (POC) can improve our understanding of unexplained RPL as aneuploidy is a common cause of RPL. Based on studies reporting results from chromosomal microarray analysis (CMA) of POC, we propose a novel algorithm for RPL evaluation. The algorithm involves following evidence-based societal guidelines (published by ASRM, ESHRE, or RCOG), excluding parental karyotyping, in combination with CMA testing of miscarriage tissue. When utilizing this new evaluation algorithm, the number of unexplained cases of RPL decreases from over 50% to less than 10%. As a result, most patients are provided an explanation for their loss and healthcare costs are potentially reduced. Patients with an otherwise negative workup with euploid POC, are classified as “truly unexplained RPL”. These patients are excellent candidates for enrollment in randomized, controlled trials examining novel immunological testing and treatment protocols.

Retrospective analysis of the prognostic factors of fetal corpus callosum dysplasia

BackgroundTo analyze the genetic characteristics and long-term outcomes of fetuses with dysplasia of the corpus callosum (DCC) or partial agenesis of the corpus callosum (PACC).MethodsA total of 42 fetuses with DCC (n = 36) or PACC (n = 6) were retrospectively analyzed from January 2016 to December 2022 at the Peking University First Hospital. The cohort was categorized into isolated (15/42, 36%) and nonisolated groups (27/42, 64%), and differences in the genetic abnormalities and long-term outcomes between the two groups were analyzed. DCC was subdivided into short CC, thin CC, and thick CC. The outcomes of the three different types of DCC were analyzed and discussed.Results(1) Thirty-nine of the 42 cases underwent CMA (chromosomal microarray analysis) and CMA + WES (whole exome sequencing), with 13/15 cases in isolated group and 26/27 cases in nonisolated group. Only pathogenic or likely pathogenic (P/LP) variants were considered, identifying P/LP variants in 2/13 cases in isolated group and 12/26 cases in nonisolated group. There was no significant difference between the two groups (χ² = 3.566, P = 0.05897). (2) In the isolated group, 8 cases were terminated, and 7 cases were delivered. Postnatal follow-up detected 1 case of gross motor development delay one year after birth; no obvious abnormalities were found in the other six cases. In the nonisolated group, 21 cases were terminated, and 6 cases were delivered. Postnatal follow-up detected 4 cases of children with different degrees of language, motor and intelligence abnormalities; 1 case died 10 days after birth. No obvious abnormalities were observed in one case. Six cases (86%, 6/7) in the isolated group showed normal development, compared with 1 case (17%, 1/6) in the nonisolated group, with a significant difference (χ² = 6.198, P = 0.01279). (3) In DCC, the delivery rates of short CCs (18 cases), thin CCs (13 cases), and thick CCs (5 cases) were 17% (3/18), 54% (7/13), and 20% (1/5), respectively, with good outcomes observed in 0% (0/3), 71% (5/7), and 0% (0/1), respectively. P/LP variants were found in 6/17 cases of short CC, 3/12 cases of thin CC, and 2/5 cases of thick CC.ConclusionsFetuses with DCC or PACC combined with other structural abnormalities had a poor long-term prognosis compared with the isolated group. Patients with thin CCs had a higher probability of a good prognosis than those with short or thick CCs.

Prenatal diagnosis and molecular cytogenetic characterization of fetuses with central nervous system anomalies using chromosomal microarray analysis: a seven-year single-center retrospective study

Few existing reports have investigated the copy number variants (CNVs) in fetuses with central nervous system (CNS) anomalies. To gain further insights into the genotype–phenotype relationship, we conducted chromosomal microarray analysis (CMA) to reveal the pathogenic CNVs (pCNVs) that were associated with fetal CNS anomalies. We enrolled 5,460 pregnant women with different high-risk factors who had undergone CMA. Among them, 57 subjects with fetal CNS anomalies were recruited. Of the subjects with fetal CNS anomalies, 23 were given amniocentesis, which involved karyotype analysis and CMA to detect chromosomal abnormalities. The other 34 cases only underwent CMA detection using fetal abortive tissue. In this study, we identified five cases of chromosome aneuploid and nine cases of pCNVs in the fetuses, with a chromosomal aberration detection rate of 24.56% (14/57). In the 23 cases that were given both karyotype and CMA analysis, one case with trisomy 18 was detected by karyotyping. Moreover, CMA revealed a further three cases of pCNVs, including the 1p36.33p36.31, 7q11.23, and 1q21.1q21.2 microdeletions, with a 13.04% (3/23) increase in CMA yield over the karyotype analysis. Additionally, three cases of trisomy 13, one case of trisomy 21, and six cases of pCNVs were detected in the other 34 fetuses where only CMA was performed. Furthermore, a higher chromosomal aberration detection rate was observed in the extra CNS anomaly group than in the isolated CNS anomaly group (40.91% vs 14.29%). In conclude, several pathogenic CNVs were identified in the fetuses with CNS anomalies using CMA. Among the detected CNVs, ZIC2, GNB1, and NSUN5 may be the candidate genes that responsible for fetal CNS anomalies. Our findings provides an additional reference for genetic counseling regarding fetal CNS anomalies and offers further insight into the genotype–phenotype relationship.

Towards solving the genetic diagnosis odyssey in Iranian patients with congenital anomalies.

Understanding the underlying causes of congenital anomalies (CAs) can be a complex diagnostic journey. We aimed to assess the efficiency of exome sequencing (ES) and chromosomal microarray analysis (CMA) in patients with CAs among a population with a high fraction of consanguineous marriage. Depending on the patient's symptoms and family history, karyotype/Quantitative Fluorescence- Polymerase Chain Reaction (QF-PCR) (n = 84), CMA (n = 81), ES (n = 79) or combined CMA and ES (n = 24) were performed on 168 probands (66 prenatal and 102 postnatal) with CAs. Twelve (14.28%) probands were diagnosed by karyotype/QF-PCR and seven (8.64%) others were diagnosed by CMA. ES findings were conclusive in 39 (49.36%) families, and 61.90% of them were novel variants. Also, 64.28% of these variants were identified in genes that follow recessive inheritance in CAs. The diagnostic rate (DR) of ES was significantly higher than that of CMA in children from consanguineous families (P = 0·0001). The highest DR by CMA was obtained in the non-consanguineous postnatal subgroup and by ES in the consanguineous prenatal subgroup. In a population that is highly consanguineous, our results suggest that ES may have a higher diagnostic yield than CMA and should be considered as the first-tier test in the evaluation of patients with congenital anomalies.

Prenatal diagnosis of dent disease type I with a nonsense pathogenic variant in CLCN5: a case study

IntroductionDent disease type I is a rare X-linked recessive renal tubular disease resulting from pathogenic variants in the CLCN5 gene. Due to the rarity of Dent disease type I and the diversity of its phenotypes, its clinical diagnosis is complex and poses a challenge to clinicians.MethodsA foetus and a child from a 36-year-old pregnant woman with a birth history of abnormal children were enrolled in this study. Pregnant women undergo amniocentesis for prenatal diagnosis at the gestational age of 12+ 3 weeks. Chromosomal microarray (CMA) analysis and whole-exome sequencing (WES) were employed to investigate the chromosomal copy number and single gene variants. Literature retrieval and data analysis were performed for genotype and phenotype collection analysis.ResultsNo chromosomal abnormalities or CNVs were detected in the entire family through karyotype and familial CMA analyses. WES identified a nonsense pathogenic variant in CLCN5 of the X chromosome, c.1942 C > T (exon 11, NM_000084), which was inherited from his mother, who exhibited regular clinical features.ConclusionThis study suggests that children with low-molecular-weight proteinuria and hypercalciuria should undergo prompt genetic testing to exclude Dent disease.

Prenatal diagnosis of fetuses with ultrasound anomalies by whole-exome sequencing in Luoyang city, China.

Background: There is a great obstacle in prenatal diagnosis of fetal anomalies due to their considerable genetic and clinical heterogeneity. Whole-exome sequencing (WES) has been confirmed as a successful option for genetic diagnosis in pediatrics, but its clinical utility for prenatal diagnosis remains to be limited. Methods: A total of 60 fetuses with abnormal ultrasound findings underwent karyotyping or chromosomal microarray analysis (CMA), and those with negative results were further subjected to WES. The identified variants were classified as pathogenic or likely pathogenic (P/LP) and the variant of uncertain significance (VUS). Pregnancy outcomes were obtained through a telephone follow-up. Results: Twelve (20%, 12/60) fetuses were diagnosed to have chromosomal abnormalities using karyotyping or CMA. Of the remaining 48 cases that underwent WES, P/LP variants were identified in 14 cases (29.2%), giving an additional diagnostic yield of 23.3% (14/60). The most frequently affected organ referred for prenatal WES was the head or neck system (40%), followed by the skeletal system (39.1%). In terms of pathogenic genes, FGFR3 was the most common diagnostic gene in this cohort. For the first time, we discovered five P/LP variants involved in SEC24D, FIG4, CTNNA3, EPG5, and PKD2. In addition, we identified three VUSes that had been reported previously. Outcomes of pregnancy were available for 54 cases, of which 24 cases were terminated. Conclusion: The results confirmed that WES is a powerful tool in prenatal diagnosis, especially for fetuses with ultrasonographic anomalies that cannot be diagnosed using conventional prenatal methods. Additionally, newly identified variants will expand the phenotypic spectrum of monogenic disorders and greatly enrich the prenatal diagnostic database.

Women's attitudes towards disclosure of genetic information in pregnancy with varying levels of penetrance.

Chromosomal-microarray-analysis (CMA) may reveal susceptibility-loci (SL) of varied penetrance for autism-spectrum-disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied. A multiple-choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance. Women's (n=941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one-quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p-values<0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR=0.37, p<0.001). Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests.

Prenatal diagnosis and outcome of pregnancy for women with high risks by screening of fetal free DNA from peripheral blood samples

To analyze the results of prenatal diagnosis and outcome of pregnancy for women with a high risk for fetal aneuploidies. A total of 747 cases of prenatal diagnosis by amniocentesis due to high risks by non-invasive prenatal testing (NIPT) were selected from January 2015 to March 2022 in the Drum Tower Hospital Affiliated to Nanjing University Medical School. The amniotic fluid samples were subjected to chromosomal karyotyping and/or chromosomal microarray analysis. All cases were followed up by searching the birth information or telephone calls, and the results were recorded. 2 test or F test were used for comparing the difference between the groups. Among the 747 pregnant women with a high risk by NIPT, 387 were true positives, and the overall positive predictive value (PPV) was 51.81%. The PPVs for trisomy 21 (T21), trisomy 18 (T18), trisomy 13 (T13) and sex chromosome aneuploidies (SCA) were 80.24% (199/248), 60% (48/80), 14% (7/50) and 38.97% (106/272), respectively. The PPV for T21 was significantly higher than T18 and T13 (χ2 = 85.216, P < 0.0001). The PPV for other chromosomal aneuploidies and copy number variations (CNVs) were 11.11% (5/45) and 40.74% (22/52), respectively. The PPV for increased X chromosomes was significantly higher than X chromosome decreases (64.29% vs. 22.22%, χ2 = 5.530, P < 0.05). The overall PPV for elder women (≥ 35 years old) was significantly higher than younger women (69.35% vs. 42.39%, χ2 = 49.440, P < 0.0001). For T21 and T18, the PPV of Z ≥ 10 group was significantly higher than that for 3 ≤ Z < 5 group or 5 ≤ Z < 10 group (P < 0.05). Among 52 cases with a high risk for CNVs, the PPV for the ≤ 5 Mb group was significantly higher than the 5 Mb < CNVs < 10 Mb or > 10 Mb groups (60% vs. 30%60% vs. 23.53%, P < 0.05). Among the 387 true positive cases, 322 had opted for induced labor, 53 had delivered with no abnormal growth and development, and 12 were lost during the follow-up. The PPVs for common chromosomal aneuploidies are related to the age and Z value of the pregnant women, which were higher in the elder group and higher Z value group. In addition, the PPV is associated with high risk types. The PPV for T21 was higher than T18 and T13, and that for 45,X was lower than 47,XXX, 47,XYY or 47,XXY syndrome. NIPT therefore has relatively high PPVs for the identification of chromosomal CNVs.

Clinical application of non-invasive prenatal testing for twin pregnancies

To evaluate the feasibility of non-invasive prenatal testing (NIPT) for the screening of fetal chromosome aneuploidies in twin pregnancies. A total of 2 745 women with twin-pregnancies were subjected for NIPT screening. Chromosomal karyotyping and chromosomal microarray analysis (CMA) were carried out on amniotic fluid samples from those with a high risk for fetal chromosome aneuploidies, and the diagnosis and pregnancy outcome were followed up. The sensitivity, specificity, positive predictive value and false positive rate of the NIPT were calculated. Compared with other chromosomal abnormalities, NIPT had a higher efficacy for trisomy 21 and sex chromosomal aneuploidy (SCA) in twin pregnancies (with sensitivity being 100%, 100%, and specificity being 99.93%, 99.9%, respectively). It is difficult to evaluate the efficacy for trisomies 18 and 13 due to the limited data. For chromosome microdeletions and microduplications spanning 15 ~ 21 Mb, NIPT also had a certain detection rate. Compared with women with natural conception, NIPT had a higher detection rate for those with twin pregnancies by assisted reproduction (P < 0.05). It is feasible to use NIPT for the detection of chromosome aneuploidies in women with twin pregnancies.

Prenatal diagnosis and outcomes in fetuses with duplex kidney.

Duplex kidney is a relatively frequent form of urinary system abnormality. This study aimed to elucidate the value of chromosomal microarray analysis (CMA) and whole exome sequencing (WES) for duplex kidney and the perinatal outcomes of duplex kidney fetuses. This retrospective cohort study included 63 patients with duplex kidney diagnosed using antenatal ultrasound between August 2013 and January 2023. We reviewed the clinical characteristics, genetic test results, and pregnancy outcomes of the patients. Among the 63 cases based on the inclusion criteria, the CMA detected seven (11.1%) clinically significant variants and nine variants of uncertain significance (VUS), and the pathogenic/likely pathogenic (P/LP) copy number variations (CNVs) in the recurrent region that were associated with prenatal duplex kidney included 17q12, 17p13.3, and 22q11.2. No significant disparity was observed in the CMA detection rate between the unilateral and bilateral groups, or between the isolated and non-isolated groups. WES identified three (50%) P/LP single-gene variants in six fetuses with duplex kidney. We detected the following pathogenic genes in the duplex kidney fetuses: KMT2D, SMPD4, and FANCI. Pregnancy termination in cases where clinically significant variants were detected by genetic testing was different in statistical significance from that in cases with negative results (9/10, 90.0% vs 8/48, 16.7%, P < 0.001). This study elucidated the value of CMA and WES for fetal duplex kidney, proving that CMA and WES may be useful tools in prenatal diagnosis and genetic counseling.

Germline mutations in cancer predisposition genes among pediatric patients with cancer and congenital anomalies.

Childhood cancer has a poorly known etiology, and investigating the underlying genetic background may provide novel insights. A recognized association exists between non-chromosomal birth defects and childhood cancer susceptibility. We performed whole-exome sequencing and chromosomal microarray analysis in a cohort of childhood cancer (22 individuals, 50% with congenital anomalies) to unravel deleterious germline variants. A diagnostic yield of 14% was found, encompassing heterozygous variants in bona fide dominant Cancer Predisposition Genes (CPGs). Considering candidate and recessive CPGs harboring monoallelic variants, which were also deemed to play a role in the phenotype, the yield escalated to 45%. Most of the deleterious variants were mapped in genes not conventionally linked to the patient's tumor type. Relevant findings were detected in 55% of the syndromic individuals, mostly variants potentially underlying both phenotypes. We uncovered a remarkable prevalence of germline deleterious CPG variants, highlighting the significance of a comprehensive genetic analysis in pediatric cancer, especially when coupled with additional clinical signs. Moreover, our findings emphasized the potential for oligogenic inheritance, wherein multiple genes synergistically increase cancer risk. Lastly, our investigation unveiled potentially novel genotype-phenotype associations, such as SETD5 in neuroblastoma, KAT6A in gliomas, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis. Novel gene-phenotype associations and candidate genes for pediatric cancer were unraveled, such as KAT6A in gliomas, SETD5 in neuroblastoma, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis. Our analysis revealed a high frequency of deleterious germline variants, particularly in cases accompanied by additional clinical signs, highlighting the importance of a comprehensive genetic evaluation in childhood cancer. Our findings also underscored the potential for oligogenic inheritance in pediatric cancer risk. Understanding the cancer etiology is crucial for genetic counseling, often influencing therapeutic decisions and offering valuable insights into molecular targets for the development of oncological therapies.

Contribution of genetic variants to congenital heart defects in both singleton and twin fetuses: a Chinese cohort study

BackgroundThe contribution of genetic variants to congenital heart defects (CHDs) has been investigated in many postnatal cohorts but described in few prenatal fetus cohorts. Overall, specific genetic variants especially copy number variants (CNVs) leading to CHDs are somewhat diverse among different prenatal cohort studies. In this study, a total of 1118 fetuses with confirmed CHDs were recruited from three units over a 5-year period, composing 961 of singleton pregnancies and 157 of twin pregnancies. We performed chromosomal microarray analysis on all cases to detect numerical chromosomal abnormalities (NCAs) and pathogenic/likely pathogenic CNVs (P/LP CNVs) and employed whole-exome sequencing for some cases without NCAs and P/LP CNVs to detect P/LP sequence variants (P/LP SVs).ResultsOverall, NCAs and P/LP CNVs were identified in 17.6% (197/1118) of cases, with NCA accounting for 9.1% (102/1118) and P/LP CNV for 8.5% (95/1118). Nonisolated CHDs showed a significantly higher frequency of NCA than isolated CHD (27.3% vs. 4.4%, p < 0.001), but there was no significant difference in the frequency of P/LP CNVs between isolated and nonisolated CHD (11.7% vs. 7.7%). A total of 109 P/LP CNVs were identified in 95 fetuses, consisting of 97 (89.0%) de novo, 6 (5.5%) parental inherited and 6 (5.5%) with unavailable parental information. The 16p11.2 proximal BP4-BP5 deletion was detected in 0.9% (10/1118) of all cases, second only to the most common 22q11.21 proximal A-D deletion (2.1%, 23/1118). Most of the 16p11.2 deletions (8/10) detected were de novo, and were enriched in CHD cases compared with a control cohort from a previous study. Additionally, SV was identified in 12.9% (8/62) of cases without NCA and P/LP CNV, most of which were de novo with autosomal dominant inheritance.ConclusionsOur cohort study provides a deep profile of the contribution of genetic variants to CHDs in both singleton and twin fetuses; NCA and P/LP CNV contribute to 9.1% and 8.5% of CHD in fetuses, respectively. We confirmed the 16p11.2 deletion as a CHD-associated hotspot CNV, second only to the 22q11.21 deletion in frequency. Most 16p11.2 deletions detected were de novo. Additionally, P/LP SV was identified in 12.9% (8/62) of fetuses without NCA or P/LP CNV.

Clinical value of screening prenatal ultrasound combined with chromosomal microarrays in prenatal diagnosis of chromosomal abnormalities

Objective To evaluate the clinical value of ultrasound findings in the screening of fetal chromosomal abnormalities and the analysis of risk factors for chromosome microarray analysis (CMA) abnormalities. Methods We retrospectively analyzed the datasets of 15,899 pregnant women who underwent prenatal evaluations at Affiliated Maternity and Child Health Care Hospital of Nantong University between August 2018 and December 2022. Everyone underwent ultrasound screening, and those with abnormal findings underwent CMA to identify chromosomal abnormalities. Results The detection rates for isolated ultrasound anomalies and combined ultrasound and CMA anomalies were 11.81% (1877/15,899) and 2.40% (381/15,899), respectively. Among all ultrasound abnormalities, detection rates for isolated ultrasound soft marker anomalies, isolated structural abnormalities, and both ultrasound soft marker anomalies with structural abnormalities were 82.91% (1872/2258), 15.99% (361/2258), and 1.11% (25/2258), respectively. The detection rate of abnormal chromosomes in pregnant women with abnormal ultrasound results was 16.87% (381/2258). The detection rates were 13.33% in cases with two or more ultrasound soft markers anomalies, 47.37% for two or more structural anomalies, and 48.00% for concomitant ultrasound soft marker and structural anomalies. Conclusions Enhanced detection rates of chromosomal anomalies in fetal malformations are achieved with specific ultrasound findings (NT thickening, cardiovascular abnormalities, and multiple soft markers) or when combined with high-risk factors (advanced maternal age, familial history, parental chromosomal anomalies, etc.). When the maternal age is over 35 and with ≥2 ultrasound soft marker anomalies accompanied with any high-risk factors, CMA testing can aid in the diagnosis of prenatal chromosomal abnormalities.

Prenatal diagnosis of chromosomal aberrations by chromosomal microarray analysis and pregnancy outcomes of fetuses with polyhydramnios

Objectives To explore the prenatal clinical utility of chromosome microarray analysis (CMA) for polyhydramnios and evaluate the short and long-term prognosis of fetuses with polyhydramnios. Methods A total of 600 singleton pregnancies with persistent polyhydramnios from 2014 to 2020 were retrospectively enrolled in this study. All cases received amniocentesis and were subjected to CMA results. All cases were categorized into two groups: isolated polyhydramnios and non-isolated polyhydramnios [with soft marker(s) or with sonographic structural anomalies]. All fetuses were followed up from 6 months to five years after amniocentesis to acquire short and long-term prognosis. Results The detection rates of either aneuploidy or pathogenic copy number variants in fetuses with non-isolated polyhydramnios were significantly higher than those with isolated polyhydramnios (5.0 vs. 1.5%, p = 0.0243; 3.6 vs. 0.8%, p = 0.0288). The detection rate of total chromosomal abnormalities in the structural abnormality group was significantly higher than that in the isolated group (10.0 vs. 2.3%, p = 0.0003). In the CMA-negative cases, the incidence of termination of pregnancy, neonatal and childhood death, and non-neurodevelopmental disorders in fetuses combined with structural anomalies was significantly higher than that in fetuses with isolated polyhydramnios (p < 0.05). We did not observe any difference in the prognosis between the isolated group and the combined group of ultrasound soft markers. In addition, the risk of postnatal neurodevelopmental disorders was also consistent among the three groups (1.6 vs. 1.3 vs. 1.8%). Conclusion For low-risk pregnancies, invasive prenatal diagnosis of isolated polyhydramnios might be unnecessary. CMA should be considered for fetuses with structural anomalies. In CMA-negative cases, the prognosis of fetuses with isolated polyhydramnios was good, and polyhydramnios itself did not increase the risk of postnatal neurological development disorders. The worse prognosis mainly depends on the combination of polyhydramnios with structural abnormalities.