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Objectives To expand the clinical phenotype spectrum and improve the understanding of prenatal ultrasound manifestations and fetal prognosis of 16p13.11 deletion/duplication syndrome in the East Asian population. Methods We conducted a comprehensive ultrasound phenotypic analysis, pedigree analysis and long-term postnatal outcome follow-up on 201 fetuses with 16p13.11 deletion/duplication, as well as on the phenotypic manifestations of 14 patients who underwent chromosomal microarray analysis between April 2013 and July 2024. Descriptive statistical analysis was used. Results The detection rates were 0.08% and 0.18%, the frequencies of de novo occurrence were 26.9% and 14.5%, and the rates of abnormal postnatal phenotypes were 25% and 17.5% in our prenatal cohort of deletion and duplication, respectively. Overall, 28.6% of deletions and 15.9% of duplications exhibited abnormal postnatal phenotypes even if they were inherited from a phenotypically normal parent. Developmental delay was the most common clinical abnormality. Immune disorders, torticollis, concealed penis and cryptorchidism were closely related phenotypes that had previously gone unnoticed. Copy number variations extending to intervals I + II or II + III appeared to be associated with a broader range of phenotypes. Isolated choroid plexus cysts may be the most relevant ultrasound soft marker for deletion, whereas isolated thickened nuchal translucency appears to be more closely associated with duplication. Cardiovascular and urinary malformations were the most frequently detected ultrasound structural abnormalities. Conclusion The large East Asian prenatal cohort is conducive to enhancing genetic counseling for 16p13.11 deletion/duplication syndrome by facilitating a more accurate prediction of fetal prognosis and developmental potential.

To examine the overall genomic copy-number variant (CNV) landscape of Chinese pediatric patients with developmental disorders. De-identified chromosomal microarray (CMA) data from 10,026 pediatric patients with developmental disorders were collected for re-evaluating the pathogenic CNV (pCNV) yields of different medical conditions and for comparing the frequency and phenotypic variability of genomic disorders between the Chinese and Western patient populations. The overall yield of pCNVs in the Chinese pediatric patient cohort was 21.37%, with variable yields for different disorders. Yields of pCNVs were positively associated with phenotypic complexity and intellectual disability/developmental delay (ID/DD) comorbidity for most disorders. The genomic burden and pCNV yield in neurodevelopmental disorders supported a female protective effect. However, the stratification analysis revealed that it was seen only in nonsyndromic ID/DD, not in nonsyndromic autism spectrum disorders or seizure. Furthermore, 15 known genomic disorders showed significantly different frequencies in Chinese and Western patient cohorts, and profiles of referred clinical features for 15 known genomic disorders were also significantly different in the two cohorts. We defined the pCNV yields and profiles of the Chinese pediatric patients with different medical conditions and uncovered differences in the frequency and phenotypic diversity of genomic disorders between Chinese and Western patients.

Background Single nucleotide polymorphism array (SNP-array) has been introduced for prenatal diagnosis. This study aims to evaluate the clinical utility of SNP-array in the prenatal central nervous system (CNS) malformations. Methods A retrospective study was conducted on 437 prenatal cases involving CNS malformations and other structural abnormalities detected by ultrasound. Samples were categorized into three groups: Single CNS malformation, Multiple CNS malformations, and CNS malformations with multiple system malformations. SNP-array and karyotype analysis were simultaneously performed on the Fetal samples. Comparative analysis of data was conducted using SPSS ( χ2 ). Results SNP-array analysis of 437 samples revealed an overall abnormality detection rate of 19.0%, which was significantly higher than the 11.7% positive rate detected by karyotype analysis in 427 samples (χ2 = 8.797, P  = 0.003). The positivity rates detected by SNP-array were 11.4%, 43.3%, and 63.0% in the above three groups, respectively, and these differences were statistically significant (χ2 = 83.247, P  = 8.379×10 − 19 ). The detection rate of clinically significant copy number variants (CNVs) (pathogenic/likely pathogenic, P/LP) was also statistically significant among the three groups (χ2 = 42.000, P  = 9.127×10 − 11 ). In pathogenic CNVs, dose-sensitive regions or genes that occur more frequently include the 4p16.3 terminal region, the 17p13.3 region, the 22q11.2 recurrent region, and DLL1, TGIF1, EBF3. We also did an analysis for pregnancy data of advanced maternal age (AMA) and found that the ratio of chromosomal abnormalities in samples was 18.8% tested by SNP-array. The postnatal follow-up data were analyzed. Compared to the group with normal chromosomal microarray analysis (CMA) result and isolated CNS malformation, the proportions of termination of pregnancy (TOP)/perinatal mortality/spontaneous abortion (27.2% vs. 69.6%, P  < 0.0001), liveborn infants requiring medical attention (6.3% vs. 21.7%, P  < 0.01), infants being alive and well at birth (66.5% vs. 8.7%, P  < 0.0001) were all statistically significant in the group with normal CMA result and non-isolated CNS malformation. The proportions of TOP/perinatal mortality/spontaneous abortion (27.2% vs. 76.7%, P  < 0.0001), infants being alive and well at birth (66.5% vs. 23.3%, P  < 0.0001) were also statistically significant in the group with abnormal CMA result and isolated CNS malformation compared to the same group mentioned above. Conclusions This study evaluated the application of SNP-array in the prenatal CNS malformations in terms of detection of positive rates, advantages in prenatal diagnosis, AMA, genotype-phenotype correlations, pregnancy outcomes and follow-up data, which could assist in the clinical diagnosis and assessment of fetal CNS malformations.

Background Autosomal recessive cutis laxa type IC (ARCL IC, MIM: #613177) results from a mutation in the LTBP4 gene (MIM: #604710) on chromosome 19q13. Case presentation A 28-day-old Chinese infant with generalized cutis laxa accompanied by impaired pulmonary, gastrointestinal, genitourinary, retinal hemorrhage, abnormality of coagulation and hyperbilirubinemia was admitted to our hospital. To find out the possible causes of these symptoms, whole-exome sequencing was performed on the infant. Two novel pathogenic frame-shift variants [c.605_606delGT (p.Ser204fs * 8) and c.1719delC (p.Arg574fs * 199)] of the LTBP4 gene associated with ARCL IC were found which was later verified by Sanger sequencing. The pathogenicity of mutations was subsequently assessed by several software programs and databases. In addition, an analytical review on the clinical phenotypes of the disease previously reported in literature was performed. Conclusions This is the first report of a Chinese infant with ARCL IC in China due to novel pathogenic variations of LTBP4 . Our study extends the cutis laxa type IC mutation spectrum as well as the phenotypes associated with the disease in different populations.

Background: To evaluate the clinical performance and clinical implementation of noninvasive prenatal testing (NIPT) using fetal fraction (FF) enrichment. Methods: Both standard NIPT and NIPT with FF enrichment were performed concurrently to 277 clinical samples. Results: On average, the FF of each sample processed by NIPT with FF enrichment was 1.9-fold higher than without enrichment. 88% (43/49) of samples with low FF in standard NIPT were recovered by the enrichment method. 11 more copy number variants (CNVs) which were confirmed by prenatal diagnosis were detected by NIPT with FF enrichment. NIPT with FF enrichment generated a positive predictive value of 75% for CNVs (≥3 Mb and 22q11.2 ≥1 Mb). NIPT with FF enrichment showed similar performance in the detection of common trisomy when compared with the standard method. Pregnant women with higher body mass indexes experienced significantly greater enriching effects on FF from NIPT with the enrichment protocol. Conclusions: NIPT with FF enrichment effectively elevated the FF level. This method is capable of detecting significantly more concordant CNVs with a positive predictive value (PPV) of 75%. Our data suggest that this enhanced version of NIPT can be used to improve the screening performance of clinically significant fetal CNVs but it should only be recommended when comprehensive counseling is available.

This study explored the associations between positive cell-free DNA (cfDNA) screening results and the decisions made by pregnant women regarding invasive diagnosis and continuation of pregnancy. We collected follow-up invasive diagnosis results, pregnancy decisions, and related clinical information for 767 singleton pregnancies with positive cfDNA screening results for common trisomies and genome-wide copy number variants (CNVs) from a cohort of 113,654 singleton pregnancies. A total of 547 (0.48%) cases of high-chance common trisomies and 220 (0.19%) cases of high-chance CNVs (≥ 3 Mb) were identified through cfDNA screening. The acceptance rate for invasive prenatal diagnosis (IPD) was 89.8% (474/520) in high-chance common trisomies and 75.9% (151/195) in those with high-chance CNVs. The positive predicted value of cfDNA screening was 65.4% for common trisomies (310/474) and 29.1% for CNVs (44/151) in this study. After IPD through SNP array-based chromosomal microarray analysis (CMA), 15.2% (23/151) of high-chance CNVs were classified as pathogenic. Eighty-three percent of pathogenicity (23/24) was observed in concordant high-chance CNVs driven by fetal signals only; 97.1% of parents chose to terminate their pregnancies with confirmed fetal common trisomies, and 95.7% of parents chose to terminate their pregnancies with confirmed pathogenic CNVs. Currently, the vast majority of cases with positive prenatal cfDNA screening findings underwent IPD. While the technical PPVs were satisfactory, the parental pregnancy choices were largely dependent on the confirmation results. Our findings further demonstrate the clinical utility of prenatal cfDNA screening for CNVs.

Congenital central hypothyroidism (CCH) is a rare disorder poorly described in childhood and adolescence. The current knowledge on the genetic bases of CCH is scarce. The purpose of this study was to analyze the clinical characteristics and molecular genetic basis of CCH in children. We conducted a thorough evaluation of the clinical features in children diagnosed with CCH. Genomic DNA was extracted from peripheral blood of both children and their parents, and chromosomal microarray analysis and whole-exome sequencing were performed. Candidates for single nucleotide variants were validated using Sanger sequencing and were classified according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines. Two cases with likely pathogenic variants were detected by whole-exome sequencing. Individual 1 carried a novel homozygous c.1418C>T (p.Ser473Phe) variant and a novel heterozygous c.416G>A. (p.Arg139Gln) variant. Individual 2 had a novel homozygous c.212C>T (p.Ala71Val) variant. The chromosomal microarray detected the presence of a 24 Mb heterozygous deletion (LOH: loss of heterozygosity) in the p12.1p13.13 region of chromosome 2 in individual 3, and the copy number variant was unknown of clinical significance. Our study employed chromosomal microarray and whole-exome sequencing to investigate central hypothyroidism in seven children, leading to the detection of genetic anomalies in three individuals. The identification of novel variants has contributed to the expanded genetic spectrum of POU1F1 and ATP6V0A4 associated with pediatric central hypothyroidism.

Background The 10q26 microdeletion syndrome (OMIM #609625) is a distinct genomic disorder characterized by a spectrum of clinical features including craniofacial anomalies, developmental delay (DD)/intellectual disability (ID), hypotonia, cardiovascular, and urogenital malformations. Despite the identification of critical regions within 10q26 linked to the syndrome's phenotype, the specific genes responsible for the associated facial characteristics, microcephaly, cognitive issues, and growth deficiencies remain elusive. Interstitial deletions at 10q25.3‐q26.3 are rare, and their contributions to 10q26 microdeletion syndrome remain unknown. Methods We conducted trio‐whole‐exome sequencing (WES) on a fetus presenting with ventricular septal defect (VSD), aortic span, intrauterine growth retardation (IUGR), and microcephaly. Variant classification was assessed according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, and the causative gene associated with cognitive phenotype was refined by means of smallest regions of overlap (SRO). Results A homozygous variant c.1544A>G (p.Tyr515Cys) in MMP21 and a large deletion at 10q26.13‐q26.2 which unmasked the homozygous mutation were identified in the proband. The maternally inherited 10q26.13q26.2 deletion was classified as likely pathogenic, while the variant c.1544A>G was of uncertain significance (VUS) based on ACMG/AMP criteria. A critical interval of approximately ~500 kb implicating the involving genes DOCK1 and INSYN2A (inhibitory synaptic factor 2A) in the cognitive phenotype of 10q26 microdeletion syndrome was refined. Conclusion This study introduces a recessive MMP21 mutation unmasked by a rare 10q26.13q26.2 deletion via WES in a Chinese fetus with congenital heart disease (CHD), IUGR, and microcephaly. We further refine INSYN2A as a potential candidate gene for cognitive phenotype in 10q26.1‐q26.3 region. Our study also highlights the utility of WES for its advantage in simultaneously analyzing both single nucleotide variants (SNVs) and copy number variants (CNVs) and provide a reference for prenatal diagnosis and genetic counseling in patients with similar conditions. This study introduces a recessive MMP21 mutation unmasked by a rare 10q26.13q26.2 deletion via WES in a Chinese fetus and further refines INSYN2A as a potential candidate gene for cognitive phenotype in 10q26.1‐q26.3 region, providing a reference for prenatal diagnosis and genetic counseling in patients with similar conditions.

Background Neuronal ceroid lipofuscinosis type 5 (CLN5) is a rare form of neuronal ceroid lipofuscinoses (NCLs) which are a group of inherited neurodegenerative diseases characterized by progressive intellectual and motor deterioration, visual failure, seizures, behavioral changes and premature death. CLN5 was initially named Finnish variant late infantile NCL, it is now known to be present in other ethnic populations and with variable age of onset. Few CLN5 patients had been reported in Chinese population. Case presentation In this paper, we report the symptoms of a Chinese patient who suffer from developmental regression and grand mal epilepsy for several years. The DNA was extracted from peripheral blood of proband and both parents, and then whole exome sequencing was performed using genomic DNA. Both sequence variants and copy number variants (CNVs) were analyzed and classified according to guidelines. As the result, a novel frameshift mutation c.718_719delAT/p.Met240fs in CLN5 and a de novo large deletion at 13q21.33-q31.1 which unmasked the frameshift mutation were identified in the proband. Despite the large de novo deletion, which can be classified as a pathogenic copy number variant (CNV), the patient’s clinical presentation is mostly consistent with that of CLN5, except for early developmental delay which is believed due to the large deletion. Both variants were detected simultaneously by exome sequencing. Conclusions This is the first report of whole gene deletion in combination with a novel pathogenic sequence variant in a CLN5 patient. The two mutations detected with whole exome sequencing simultaneously proved the advantage of the sequencing technology for genetic diagnostics.

Background Cri-du-chat syndrome (CdCS; OMIM#123450) is a classic contiguous gene syndrome caused by chromosome 5p terminal deletion (5p-), which characterized by a high-pitched cat-like cry, developmental delay, severe psychomotor, mental retardation, and dysmorphic features in infancy. Prenatal diagnosis of CdCS is difficult due to the non-specific ultrasound features. And reports using array analysis are rare. This study presented the first retrospective analysis of prenatal series of CdCS fetuses diagnosed by single nucleotide polymorphism (SNP) array in China. Case presentation A total of 35,233 pregnant women were enrolled from Jan 2014 to April 2019 in our center, there are twelve 5p- cases with abnormal sonographic signs revealed by SNP array, giving an incidence of 0.034% (12/35,233). Clinical information and molecular basis included: maternal demographics, indications for invasive testing, sonographic findings and SNP array results. Among all the 5p- cases revealed, nine cases were diagnosed by both karyotyping and SNP array, three cases were detected only by SNP array. Half of our cases (6/12) had an isolated 5p terminal deletion, which sizes ranged from 9.0 Mb to 30 Mb. The other half of cases (6/12) characterized by unbalanced translocation, with sex ratio 7:5 (female: male), when combine the clinical features observed from this study and available literature, the most frequent anomaly observed in prenatal ultrasound examination of CdCS was cerebral abnormalities, accounted for 44.4% (16/36) of the existing cases. Features that are less consistent included: choroid plexus cyst (13.8%, 5/36), single umbilical artery (13.3%, 4/30), ventricular septal defect (11.1%, 4/36), hydrops fetalis (8.3%, 3/36), ascites (8.3%, 3/36), increased NT/NF (8.3%, 3/36), absent/severely hypoplastic nasal bone (5.5%, 2/36), in order. Conclusion Prenatal findings such as cerebral abnormalities, absent/hypoplastic nasal bone, hydrops fetalis, ascites or encephalocele may act as suggestive signs of CdCS or other microdeletion/duplication syndromes. Combining typical karyotyping with chromosomal microarray analysis (CMA) is a definitive method for a precise diagnosis of CdCS and provides more accurate results in order to offer genetic counseling to families which need to deal with cryptic aberrations.