The actin cytoskeleton is regulated by many proteins including capping proteins that stabilize actin filaments (F-actin) by inhibiting actin polymerization and depolymerization. Here, we report two pediatric probands who carry damaging heterozygous de novo mutations in CAPZA2 (HGNC: 1490) and exhibit neurological symptoms with shared phenotypes including global motor development delay, speech delay, intellectual disability, hypotonia and a history of seizures. CAPZA2 encodes a subunit of an F-actin-capping protein complex (CapZ). CapZ is an obligate heterodimer consisting of α and β heterodimer conserved from yeast to human. Vertebrate genomes contain three α subunits encoded by three different genes and CAPZA2 encodes the α2 subunit. The single orthologue of CAPZA genes in Drosophila is cpa. Loss of cpa leads to lethality in early development and expression of the human reference; CAPZA2 rescues this lethality. However, the two CAPZA2 variants identified in the probands rescue this lethality at lower efficiency than the reference. Moreover, expression of the CAPZA2 variants affects bristle morphogenesis, a process that requires extensive actin polymerization and bundling during development. Taken together, our findings suggest that variants in CAPZA2 lead to a non-syndromic neurodevelopmental disorder in children.

Chromosomal mosaicism remains a perpetual diagnostic and clinical dilemma. In the present study, we detected two prenatal trisomy 9 mosaic syndrome cases by using multiple genetic testing methods. The non-invasive prenatal testing (NIPT) results suggested trisomy 9 in two fetuses. Karyotype analysis of amniocytes showed a high level (42%–50%) of mosaicism, and chromosomal microarray analysis (CMA) of uncultured amniocytes showed no copy number variation (CNV) except for large fragment loss of heterozygosity. Ultrasound findings were unmarkable except for small for gestational age. In Case 1, further umbilical blood puncture confirmed 22.4% and 34% trisomy 9 mosaicism by CMA and fluorescent in situ hybridization (FISH) respectively. After comprehensive consideration of the genetic and ultrasound results, the two gravidas decided to receive elective termination and molecular investigations of multiple tissue samples from the aborted fetus and the placenta. The results confirmed the presence of true fetoplacental mosaicism with levels of trisomy 9 mosaicism from 76% to normal in various tissues. These two cases highlight the necessity of genetic counseling for gravidas whose NIPT results highly suggest the risk of chromosome 9 to ascertain the occurrence of mosaicism. In addition, the comprehensive use of multiple genetic techniques and biological samples is recommended for prenatal diagnosis to avoid false-negative results. It should also be noted that ultrasound results of organs with true trisomy 9 mosaicism can be free of structural abnormalities during pregnancy.

Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by functional deficiency of propionyl-CoA carboxylase, clinically character

Background: Heterozygous pathogenic variants in WBP11 , a spliceosome-associated gene, have recently been linked to VACTERL syndrome, yet prenatal manifestations and genotype–phenotype correlations remain poorly characterized. Methods: Genomic DNA was extracted from fetal tissues, amniotic fluid cells, or peripheral blood samples for trio-based whole-exome sequencing (WES) to identify potential genetic etiologies. The structural stability of the WBP11 protein associated with missense variants was characterized using 3D protein structural modeling. The impact of splicing variant was further evaluated through TA cloning coupled with Sanger sequencing. Results: Here, we report the first case series of WBP11 -related disorder in Chinese patients, comprising four fetuses and one postnatal child from five unrelated families. Whole-exome sequencing identified five previously unreported heterozygous WBP11 variants (NM_016312.3), including three nonsense (p.Arg55*, p.Lys83*, p.Ser279*), one canonical splice-site (c.1310-1G > A), and one missense (p.Arg91Cys). Three occurred de novo, while two were paternally inherited from clinically unaffected or mildly affected carriers, supporting incomplete penetrance. Crucially, RNA analysis of amniocytes carrying the c.1310-1G > A variant revealed only 4% aberrant splicing (c.1310del, p.Gly437Glufs*6), explaining the mild fetal phenotype of isolated femoral shortening and challenging conventional assumptions about the pathogenicity of canonical splice-site variants. The postnatal patient primarily presents with retinal pigmentary degeneration, hearing impairment, bilateral cryptorchidism, short stature, and global developmental delay. Most of these features have been reported in WBP11 -related cases but are not considered classic diagnostic criteria for VACTERL. Notably, prenatal cases predominantly presented with cardiac malformations, whereas vertebral anomalies, common postnatally, were absent prenatally, suggesting age-dependent phenotypic evolution. Conclusions: We have documented the retinal pigment phenotype in WBP11 mutant patients for the first time. Our findings expand the mutational and clinical spectrum of WBP11 -related disease, highlight the limitations of sequence-based variant interpretation without functional or transcriptomic validation, and underscore the necessity of integrating detailed phenotypic correlation into prenatal genetic counseling.