Background: Congenital hydrocephalus‐3 with brain anomalies (HYC3, MIM 617967) is a rare form of congenital hydrocephalus characterized by severe hydrocephalus and cerebellar abnormalities, the onset of the disease occurs in utero even resulting in fetal death. A very limited spectrum of WDR81 pathogenic variants had been reported in three unrelated families with HYC3. This study aims at presenting novel compound heterozygous frameshift variants in WDR81 in a Chinese fetus.Methods: Whole‐exome sequencing (WES) was performed for a fetus with multiple congenital anomalies including sever hydrocephalus, cleft lip and palate, hydrops fetalis, hepatomegaly, and cerebellar hypoplasia. Sanger sequencing was performed to confirm the origin of the variants subsequently. Variants classification was based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.Results: Two novel heterozygous variants c.146_147insG (p.Thr52fs) and c.673delC (p.Leu225fs) in WDR81 were identified. Sanger sequencing revealed that the c.146_147insG mutation was maternal origin and the c.673delC mutation was paternal origin. Both variants were pathogenic according to the ACMG/AMP guidelines.Conclusion: The present study expands the mutation spectrum of WDR81 and help further define the genotype–phenotype correlations of HYC3. WDR81‐related HYC3 were highly clinical heterogeneity. We suggested that fetal hydrocephalus with extracerebral manifestations may be suggestive of WDR81 deficiency and WES is effective for achieving a conclusive diagnosis for disorder.

The WDR19 gene has been reported to be involved in nephronophthisis-related ciliopathies such as isolated nephronophthisis 13 (NPHP13), Sensenbrenner syndrome, Jeune syndrome, Senior-Loken syndrome, Caroli disease, retinitis pigmentosa and Asthenoteratospermia. In the present study, we provided the detailed clinical characteristics and genetic analysis of a patient with four variants in WDR19 and TG, reviewed a comprehensive mutation analysis in the WDR19-related ciliopathies, discussed the relationship between genotype and phenotype, and compared the allele frequencies (AFs) of WDR19 variants depending on the ethnic background. We used whole-exome sequencing (WES) combined with bioinformatics analysis to investigate the genetic variants of a 3-year-old boy with common features of WDR19-associated NPHP13 and Caroli disease, bilateral central blindness, refractory epilepsy, and elevated thyroid stimulating hormone. A novel splice-donor variant, c.98+1G > C, and a recurrent missense variant, c.3533G > A, were identified in the WDR19 gene. We used effective mRNA analysis to verify the effects on pre-mRNA processing and to assess the pathogenicity of the splice-site variant. The patient also harbored compound heterozygous variants of the TG gene (c.4889A > G, c.274+2T > G). Of note, using a review of an in-house database, we identified four additional likely pathogenic WDR19 variants and estimated the overall AF of WDR19 mutations to be 0.0025 in the southern Chinese population. Our findings have expanded the allelic spectrum of mutations in the WDR19 gene and broadened the clinical phenotype spectrum of WDR19-related ciliopathies. The results have also provided new insights into the clinical heterogeneity of the disorder, which would be useful in accurate genetic counseling for affected individuals and carrier screening in a general population.

Background: Nemaline myopathy 8 is a severe autosomal recessive muscle disorder characterized by fetal akinesia or hypokinesia, contractures, fractures, respiratory failure and swallowing difficulties apparent at birth.Methods: An affected dizygotic twin pair from a non‐consanguineous Chinese family presented with severe asphyxia, lethargy and no response to stimuli. The dysmorphic features included prominent nasal bridge, telecanthus, excessive hip abduction, limb edema, absent palmar and sole creases, acromelia, bilateral clubfoot, appendicular hypertonia and cryptorchidism. Both infants died in the first week of life. Whole‐exome sequencing was used to identify the causative gene.Results: Whole‐exome sequencing identified a recurrent missense variant c.1516A>C and a novel splice‐acceptor variant c.1153‐1G>C in KLHL40 gene in both siblings. We estimated the disease incidence in Southern Chinese population to be 2.47/100,000 based on the cumulative allele frequency of pathogenic and likely pathogenic variants in our internal database.Conclusion: Our study expanded the mutation spectrum of KLHL40 and the condition could have been underdiagnosed before. We identified a recurrent missense variant c.1516A>C and provided evidence further supporting the founder effect of this variant in Southern Chinese population. Given the severity of the condition and the relative high incidence, this not‐so‐rare disorder should be included in expanded carrier screening panel for Chinese population.

Background and Objectives Clark-Baraitser syndrome is characterized by intellectual disability with or without autism spectrum disorders, speech delay, motor delay, behavioral abnormalities, and facial dysmorphism. It is caused by a heterozygous pathogenic variant in the thyroid hormone receptor interactor 12 (TRIP12) gene. However, loss of function and haploinsufficiency are the pathogenic mechanisms behind the TRIP12-related disorder. Methods We conducted an exome sequencing analysis for 2 unrelated patients with moderate intellectual disability, speech delay, and motor delay. Results We identified 2 de novo TRIP12 mutations in these 2 patients. One patient had a frameshift duplication, whereas the other had a synonymous variant. Both patients presented with common features of the syndrome, but clinical heterogeneity has been also observed between them. For the synonymous variant, reverse transcription PCR in RNA extracted from leukocytes demonstrated the presence of a truncated messenger RNA (mRNA) transcript that skipped exon 12. This transcript escapes degradation at the mRNA level. To assess the effect of the synonymous substitute on TRIP12 proteolytic activity, the expression of 9 known responsive genes at the mRNA level was measured, of which 3 genes were upregulated at least 2-fold in the patient. Discussion We reported 2 patients with Clark-Baraitser syndrome caused by novel synonymous and frameshift variants in the TRIP12 gene, and our study expands the mutation spectrum of the TRIP12 gene. This study will help to improve our understanding of variable phenotypic presentations in TRIP12-related disorders.

Background: Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified.Methods: We described an HGPPS patient and performed whole‐exome sequencing (WES) to identify the causative gene.Results: We identified a missense variant and a splice‐site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention of 700 bp from intron 17, which was caused by a variation in the noncanonical splicing site. We identified five additional ROBO3 variants, which were likely pathogenic, and estimated the overall allele frequency in the southern Chinese population to be 9.44 × 10⁻⁴, by a review of our in‐house database.Conclusion: This study has broadened the mutation spectrum of the ROBO3 gene and has expanded our knowledge of variants in noncanonical splicing sites. The results could help to provide more accurate genetic counseling to affected families and prospective couples. We suggest that the ROBO3 gene should be included in the local screening strategy.