Rare IFT140-Associated Phenotype of Cranioectodermal Dysplasia and Features of Diagnostic Journey in Patients with
Margarita Sharova1, Tatyana Markova1, Maria Sumina2
1Research Centre for Medical Genetics, 115522 Moscow, Russia.
Insights
Pathogenic variants in the IFT140 gene cause cranioectodermal dysplasia, a condition with varied symptoms. Identifying complex genetic changes like tandem duplications is crucial for accurate diagnosis and family genetic counseling.
Area of Science:
- Genetics
- Molecular Biology
- Clinical Medicine
Background:
- Mainzer-Saldino syndrome is typically associated with pathogenic variants in the IFT140 gene.
- Cranioectodermal phenotypes linked to IFT140 variants are rare, with few cases previously reported.
- Understanding genotype-phenotype correlations is vital for rare genetic disorders.
Observation:
- A patient presented with a cranioectodermal phenotype, skeletal features, and early-onset end-stage renal failure requiring kidney transplantation.
- This patient lacked common ophthalmological features like retinopathy or optic nerve atrophy seen in other IFT140-related cases.
- Diagnostic challenges included identifying a splicing variant and an exons 27-30 tandem duplication via exome sequencing and whole genome sequencing.
Findings:
- Two additional patients with Mainzer-Saldino syndrome showed typical features but required whole genome sequencing to detect a tandem duplication missed by initial panel or exome sequencing.
- The study highlights the importance of comprehensive genetic analysis, including whole genome sequencing, to uncover complex variants like tandem duplications.
- The identified variants in IFT140 contribute to the phenotypic variability observed in cranioectodermal dysplasia.
Implications:
- Accurate identification of IFT140 variants, including structural variations, is essential for precise genetic diagnosis.
- Recognizing the polymorphism in IFT140-related cranioectodermal phenotypes aids in providing effective genetic counseling.
- This research emphasizes the need for advanced genetic testing strategies to ensure correct diagnostic pathways for patients with IFT140 variants.
Abstract:
Here we present a patient with a cranioectodermal phenotype associated with pathogenic variants in the IFT140 gene. Most frequently, pathogenic variants in IFT140 correspond to the phenotype of Mainzer-Saldino syndrome. Only four patients have previously been described with this cranioectodermal phenotype and variants in IFT140. In comparison to other IFT140-cranioectodermal patients, our proband had similar skeletal features among with early onset end-stage renal failure that required kidney transplantation but did not have common ophthalmological features such as retinopathy, optic nerve atrophy, or nystagmus. Following exome sequencing, a splicing variant and exons 27-30 tandem duplication were suspected and further validated. The two other patients with Mainzer-Saldino syndrome that we described displayed a typical clinical picture but a special diagnostic journey. In both cases, at first only one pathogenic variant was detected following panel or exome NGS sequencing. Further WGS was performed for one of them where tandem duplication was found. Screening the third patient for the same tandem duplication was successful and revealed the presence of this duplication. Thus, we suggest that the description of the clinical feature polymorphism in a rare IFT140-cranioectodermal phenotype is extremely important for providing genetic counseling for families, as well as the formation of the correct diagnostic path for patients with a variant in IFT140.
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