A novel mutation within intron 17 of the CUL7 gene results in appearance of premature termination codon

Guo, Liangjie; Feng, Zhanqi; Jin, Xiaoye; Yin, Shanshan; Zhang, Mengting; Y, Gao; Zhang, Bo; Wang, Hongdan; Liu, Lin

doi:10.1016/j.cca.2020.04.008

Cited by 3 publications

(3 citation statements)

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“…The splicing patterns of pre-mRNA can also be measured by minigene assay in vitro. As a rapid and efficient experimental method, minigene has been increasingly used to study the effect of variants on splicing in vitro, especially when endogenous mRNA is difficult to obtain [25, 26]. In addition, its positive results can provide additional evidence for pathogenicity classification according to the ACMG guideline [27].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Splicing Variant c.3813-3A>G in NPHP3 by Reanalysis of Whole Exome Sequencing in a Chinese Boy with Nephronophthisis

Zhang¹,

Zhi²,

Wang³

et al. 2023

Nephron

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Nephronophthisis is an autosomal recessive cystic kidney disease characterized by tubular injury and commonly results in kidney failure. We reported a case of 4-year-old Chinese boy presented with severe anemia, kidney and liver dysfunction. Whole exome sequencing (WES) was performed to identify the candidate variant with a negative result initially. After complete collection of clinical information, reanalysis of WES identified a homozygous NPHP3 variant c.3813-3A>G (NM_153240.4). The effect on mRNA splicing of the intronic variant was predicted through software (three in silico splice tools). Furthermore, in vitro minigene assay was conducted to validate the predicted deleterious effects of the intronic variant. All of the splice prediction programs and minigene assay indicated that the variant had an impact on the normal splicing pattern of NPHP3. Our study confirmed the effect of the c.3813-3A>G variant on NPHP3 splicing in vitro, which gives additional evidence for the clinical significance of the variant and provides a basis for genetic diagnosis of nephronophthisis 3. In addition, we think that it is essential to reanalyze WES data after the complete clinical information collection to avoid missing some important candidate variants.

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Section: Discussionmentioning

confidence: 99%

Identification of a Splicing Variant c.3813-3A>G in NPHP3 by Reanalysis of Whole Exome Sequencing in a Chinese Boy with Nephronophthisis

Zhang¹,

Zhi²,

Wang³

et al. 2023

Nephron

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“…Prenatally, the presence of shortened long bones may suggest conditions such as osteogenic imperfecta or achondroplasia, which are not specific to 3M syndrome. Eight cases of 3M syndrome in fetuses have been diagnosed, and additional features have been reported in seven cases (Chincoli et al., 2014; Guo et al., 2020; Hu et al., 2017; Huang et al., 2023; Huber et al., 2009; Meo et al., 2000; Smogavec et al., 2022): two fetuses exhibited increased nuchal translucency (NT; Guo et al., 2020; Huang et al., 2023); two fetuses had a hypoplastic thorax; one had short nasal bones (Meo et al., 2000; Smogavec et al., 2022); one fetus had head frontal bossing and bilateral temporal bone depression (Hu et al., 2017); and one had characteristic facial features, prominent heels, and slender long bones (Huber et al., 2009). The increased NT should be distinguished from RASopathies, and most RASopathies do not exhibit severely short long bones during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Prenatal diagnosis and preimplantation genetics testing of 3M syndrome in a Chinese family with novel biallelic variants of CUL7

Wang,

He,

Wang

et al. 2023

Molec Gen & Gen Med

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Background3M syndrome is a rare autosomal recessive developmental disorder characterized by pre and postnatal growth deficiency, dysmorphic facial features, and normal intelligence. 3M syndrome should be suspected in a proband with a combination of characteristic or recognizable dysmorphic features. The diagnosis of 3M syndrome could be confirmed by identifying biallelic variants in CUL7, OBSL1, or CCDC8.MethodsWhole‐exome sequencing (WES) was performed to identify genetic causes. Reverse‐transcription polymerase chain reaction (RT‐PCR) was performed to detect aberrant splicing events. Haplotypes were constructed using multiplex PCR and sequencing. Variants of the parental haplotype and target likely pathogenic variants were detected by PCR and Sanger sequencing from the embryos. Copy number variant (CNV) detection was performed by next‐generation sequencing.ResultsWe present the case of a nonconsanguineous Chinese couple with one abnormal pregnancy, where the fetus showed 3M phenotypes of shortened long bones. WES identified two novel heterozygous mutations in CUL7: NM_014780.5:c.354del (p.Gln119ArgfsTer52) and NM_014780.5:c.1373‐15G>A. RT‐PCR from RNA of the mother's peripheral blood leucocytes showed that c.1373‐15G>A caused the insertion of a 13‐bp extra intron sequence and encoded the mutant p.Leu459ProfsTer25. Both variants were classified as likely pathogenic according to ACMG/AMP guidelines and Clinical Genome Resource specifications. During genetic counseling, the options of prenatal diagnosis through chorionic villus sampling or amniocentesis, adoption, sperm donation, and electing not to reproduce, as well as preimplantation genetic testing for monogenic disorders (PGT‐M), were discussed. The couple hopes to conceive a child of their own and refused to accept the 25% risk during the next pregnancy and opted for PGT‐M. They finally successfully delivered a healthy baby through PGT‐M.ConclusionThis study expanded the mutation spectrum of CUL7, detected the aberrant splicing event of CUL7 via RT‐PCR, constructed the haplotype for PGT‐M, and demonstrated the successful delivery of a healthy baby using PGT‐M.

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“…Previously, diagnosis of 3M syndrome depended primarily on clinical manifestations and radiographic examination. With the development of gene diagnosis technology, variants in the CUL7, OBSL1, and CCDC8 genes have been identified as responsible for 3M syndrome (Guo et al, 2020). In 2005, Huber et al (2019 initially reported that CUL7 variants accounted for 77.5%, OBSL1 variants 16.3%, and CCDC8 variants 6%, of 3M syndrome cases; however, with continued research, changes in CUL7 were found to be responsible for the majority of cases, while OBSL1 mutations were present in more than 16.3% and those in CDCC8 less than 6%.…”

Section: Introductionmentioning

confidence: 99%

Chinese patients with 3M syndrome: clinical manifestations and two novel pathogenic variants

Xu,

Liu,

Yang

et al. 2023

Front. Genet.

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Background: 3M syndrome is a rare autosomal recessive disease, characterized by intrauterine and postnatal growth retardation, facial dysmorphism, large head circumference, and skeletal changes, has rarely been reported in the Chinese population.Methods: We describe the clinical manifestations and gene variants in four sporadic cases of 3M syndrome in Chinese individuals from different families.Results: All cases had significant growth retardation, relative macrocephaly, and typical facial features. Exome sequencing revealed that two patients with 3M syndrome had homozygous variants of the CUL7 gene: one novel pathogenic variant and one previously reported pathogenic variant; the other two patients were heterozygous for variants in OBSL1, one of which had not been reported previously. Clinical evaluation indicated that these Chinese patients with 3M syndrome shared similar recognizable features with those reported in patients of other ethnic backgrounds, but not all patients with 3M syndrome in this study had normal development milestones. Two patients underwent recombinant human growth hormone (rhGH) therapy and showed accelerated growth in the first 2 years; however, the growth rate slowed in the third year in one case. There were no obvious adverse reactions during rhGH treatment.Conclusion: We report one novel CUL7 and one novel OBSL1 mutation in patients with 3M syndrome. Children with short stature, specific facial features, and physical symptoms should be referred for genetic testing to obtain precise diagnosis and appropriate treatment. The effects of rhGH treatment on adult height requires long-term observation and study in a large sample.

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A novel mutation within intron 17 of the CUL7 gene results in appearance of premature termination codon

Cited by 3 publications

References 18 publications

Identification of a Splicing Variant c.3813-3A>G in NPHP3 by Reanalysis of Whole Exome Sequencing in a Chinese Boy with Nephronophthisis

Identification of a Splicing Variant c.3813-3A>G in NPHP3 by Reanalysis of Whole Exome Sequencing in a Chinese Boy with Nephronophthisis

Prenatal diagnosis and preimplantation genetics testing of 3M syndrome in a Chinese family with novel biallelic variants of CUL7

Chinese patients with 3M syndrome: clinical manifestations and two novel pathogenic variants

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A novel mutation within intron 17 of the CUL7 gene results in appearance of premature termination codon

Cited by 3 publications

References 18 publications

Identification of a Splicing Variant c.3813-3A&gt;G in NPHP3 by Reanalysis of Whole Exome Sequencing in a Chinese Boy with Nephronophthisis

Identification of a Splicing Variant c.3813-3A&gt;G in NPHP3 by Reanalysis of Whole Exome Sequencing in a Chinese Boy with Nephronophthisis

Prenatal diagnosis and preimplantation genetics testing of 3M syndrome in a Chinese family with novel biallelic variants of CUL7

Chinese patients with 3M syndrome: clinical manifestations and two novel pathogenic variants

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Product

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Identification of a Splicing Variant c.3813-3A>G in NPHP3 by Reanalysis of Whole Exome Sequencing in a Chinese Boy with Nephronophthisis

Identification of a Splicing Variant c.3813-3A>G in NPHP3 by Reanalysis of Whole Exome Sequencing in a Chinese Boy with Nephronophthisis