Intellectual disability (ID) is a common disease. While the etiology remains incompletely understood, genetic defects are a major contributor, which include mutations in genes encoding zinc finger proteins. These proteins modulate gene expression via binding to DNA. Consistent with this knowledge, we report here the identification of mutations in the ZNF407 gene in ID/autistic patients. In our study of an ID patient with autism, a reciprocal translocation 46,XY,t(3;18)(p13;q22.3) was detected. By using FISH and long-range PCR approaches, we have precisely mapped the breakpoints associated with this translocation in a gene-free region in chromosome 3 and in the third intron of the ZNF407 gene in chromosome18. The latter reduces ZNF407 expression. Consistent with this observation, in our subsequent investigation of 105 ID/autism patients with similar clinical presentations, two missense mutations Y460C and P1195A were identified. These mutations cause non-conservative amino acid substitutions in the linker regions between individual finger structures. In line with the linker regions being critical for the integrity of zinc finger motifs, both mutations may result in loss of ZNF407 function. Taken together, we demonstrate that mutations in the ZNF407 gene contribute to the pathogenesis of a group of ID patients with autism.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by obesity, mental retardation, retinal dystrophy, hypogenitalism and renal and polydactyly malformations. The last two malformations may be observed antenatally and are highly variable, making the prenatal diagnosis of BBS challenging. The present study investigated the molecular etiology of BBS and validated a method for prenatal diagnosis. A Chinese couple who had conceived two fetuses with multiple malformations, including hyperechogenic kidneys, polydactyly, cardiac malformation and abdominal abnormalities, presented at the Prenatal Diagnosis Center of Boai Hospital of Zhongshan Affiliated to Southern Medical University (Zhongshan, China) in November 2018. BBS was suspected and whole-exome sequencing was performed for the second fetus. Two novel compound heterozygous variants were detected in the BBS10 gene, c.784_785delGA from the father and c.1812dupT from the mother, which are probably causative of the pathogenesis of BBS. This finding provided a basis for genetic counseling and prenatal diagnosis for the couple and enriched the variation spectrum of the BBS10 gene. The ultrasonic findings of the fetal abdomen are the first reported in fetuses with BBS, expanding the antenatal phenotypes of BBS.

The proband with congenital heart disease and abnormal thumb was clinically diagnosed as Holt–Oram syndrome (HOS). A novel variant, T‐box transcription factor 5 (TBX5) c.755 + 1 G > A, was identified in the proband via whole exome sequencing and validated using Sanger sequencing. Pedigree analysis and clinical examinations revealed three/seven individuals over three generations within the family, with features suggestive of HOS. Deep amplicon sequencing confirmed that the allele frequencies of the novel variant in the proband (III‐1), her brother (III‐2), and her mother (II‐2) were 50%, 48.3%, and 38.1%, respectively, indicating that III‐1 and III‐2 harbored heterozygous variants, while II‐2 harbored mosaic heterozygous variants. The minigene splicing assay showed that the novel variant affected the normal splicing of exon 7, resulting in the production of abnormal TBX5 transcripts. Reverse transcription‐quantitative polymerase chain reaction and western blot analyses revealed that the novel variant upregulated TBX5 expression at the transcriptional and translational levels. Nuclear localization assay demonstrated impaired nuclear localization of the mutant TBX5. Cell viability assay revealed the inhibition of cell activity by the mutant TBX5. Our findings indicate that the novel variant was potentially induced HOS, probably by causing aberrant splicing, reducing the enrichment of nuclear TBX5 protein, and inhibiting cellular proliferation.

Recent studies showed that germline, bi-allelic and pathogenic variants of the WWOX gene have been associated with spinocerebellar ataxia type 12 (SCAR12) and a severe WWOX-related epileptic encephalopathy (WOREE syndrome). The underlying mechanisms of the diseases are poorly understood. Here, we reported the case of a WOREE syndrome patient with early-onset refractory seizures and global neurodevelopmental delay who died at the age of two and a half years. The whole exon sequencing showed homozygous exon 6 deletions in the WWOX gene. Quantitative real-time polymerase chain reaction (PCR) confirmed that deletions were inherited from each parent. An exons 6–8 deletion was inherited from the mother, while an exon 6 deletion plus a microdeletion involving intron 5 was inherited from the father. Due to the structure of the WWOX locus encompassing the FRA16D fragile site, we confirmed the exact breakpoints using whole genomic sequencing combined with long-range PCR. Our findings extend the mutation spectrum of the WOREE syndrome and support an important role for the WWOX gene in neural development.

A Norrie disease protein gene (NDP) variant, c.174 + 1G > A, was found in a Chinese family through next-generation sequencing and verified with Sanger sequencing. A case of Norrie disease was reported in the first child, and the symptoms were consistent with the results of gene sequencing. The child’s mother, who was pregnant at the time, was found to be a carrier of the identified pathogenic variant. To determine if the fetus carried the same disease-causing variant, prenatal examination and prenatal diagnosis were conducted. The fetus had biocular vitreous abnormalities and complete retinal abnormalities. Genetic testing showed that the fetus had maternally inherited the NDP gene variant found in the proband. It was concurrently confirmed that the NDP gene variant led to the deletion of 246 bp at the 3′ end of exon 2, resulting in the deletion of the initiation codon and the occurrence of disease. Our study suggests that the diagnosis of rare diseases through next-generation sequencing, combined with prenatal ultrasound and prenatal diagnosis, can help families with known familial genetic diseases. Furthermore, the findings of this study broaden the known genetic spectrum of Norrie disease.

Background WWOXbiallelic and loss-of-function pathogenic variants cause WWOX-related epileptic encephalopathy (WOREE syndrome), which has been reported in 60 patients to date. In this study, we report on a WOREE syndrome patient who presented with early-onset refractory seizures and global neurodevelopmental delay and died at the age of two and a half years. Methods We present clinical and molecular findings in the patient, including biallelic pathogenic variants in the WWOX gene. We employed different molecular approaches, such as whole exon sequencing, quantitative real-time polymerase chain reaction (PCR), and whole-genome sequencing, to identify the genetic defects. The breakpoints were determined through gap PCR and Sanger sequencing. Result Whole exon sequencing revealed homozygous exon 6 deletions in the WWOX gene in the proband. Quantitative real-time PCR confirmed that the deletions were inherited from each parent. However, using whole-genome sequencing, we identified three larger deletions (intron 5, exon 6, and exon 6-8) involving the WWOX gene in the proband, with deletion sizes of 13,261, 53,904, and 177,200 bp. The exact breakpoints were confirmed through gap PCR and Sanger sequencing. We found that the proband inherited the discontinuous deletion of intron 5 and exon 6 from the father, and the exons 6-8 deletion from the mother using gap PCR. Conclusion Our findings extend the variant spectrum of WOREE syndrome and support the critical role of the WWOX gene in neural development.