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Jun 19, 2023

Rare IFT140-Associated Phenotype of Cranioectodermal Dysplasia and Features of Diagnostic Journey in Patients with Suspected Ciliopathies

Margarita Sharova, Tatyana Markova, Maria Sumina, Marina Petukhova, Maria Bulakh, Oxana Ryzhkova, Tatyana Nagornova, Sofya Ionova, Andrey Marakhonov, Elena Dadali, Sergey Kutsev | Genes | 20 June 2023 | Vol 14 (8) | page 1553 |doi.org/10.3390/genes14081553


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.


1. Introduction

The IFT140 gene encodes for the IFT140 protein, which is part of a large multi-protein complex called the intraflagellar transport (IFT) complex. This complex is essential for the formation, maintenance, and function of the cilia, which are hair-like structures that extend from the surface of diverse types of cells. Biallelic pathogenic variants in IFT140 or other IFT-A complex genes can cause defective retrograde cilial transport [1]. This can result in a range of disorders known as ciliopathies, which can affect multiple organ systems and cause a variety of symptoms, including vision and hearing loss, skeletal abnormalities, kidney disease, and developmental delay [2,3].


The IFT140 gene is associated with several different phenotypes, such as Short-rib thoracic dysplasia, type 9 syndrome (OMIM #266920), and Retinitis pigmentosa, type 80 (OMIM #617781), as per OMIM database. Short-rib thoracic dysplasia, type 9 syndrome encompasses phenotypic spectrum from less severe Mainzer–Saldino syndrome to asphyxiating thoracic dystrophy or Jeune syndrome. Mainzer–Saldino syndrome (MSS) is characterized by a combination of the cone-shaped epiphyses of the phalanges, early onset of renal failure, and retinal dystrophy. Symptoms of thoracic dysplasia are not dominant in the phenotype and patients can develop a narrow chest and recurrent respiratory infections without asphyxia or other severe symptoms. Occasionally, patients can present liver fibrosis, mild developmental delay, and cerebellar ataxia [4,5]. More than 40 variants in the IFT140 gene have been described in patients with MSS or other short-rib thoracic dysplasia phenotypes, according to the HGMD database to date (2022.1 version).


Additionally, according to recent publications, the IFT140 gene is associated with another newly described phenotype called Cranioectodermal dysplasia or Sensenbrenner syndrome [6,7,8]. Cranioectodermal dysplasia (CED) is characterized by the combination of MSS symptoms with craniofacial abnormalities (frontal bossing, dolichocephaly, sagittal craniosynostosis, epicanthal folds, telecanthus, hypertelorism) and ectodermal anomalies (sparse and thin hair, dental hypoplasia, oligodontia, nail dysplasia) [9,10]. There are only a few patients described in the literature with CED associated with the IFT140 gene [6,7,8].


Here, we present the fifth patient with IFT140 CED phenotype. We compared this patient with two other MSS patients with IFT140 variants in our cohort and their diagnostic journeys.



 

References

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  2. Waters, A.M.; Beales, P.L. Ciliopathies: An Expanding Disease Spectrum. Pediatr. Nephrol. 2011, 26, 1039–1056.

  3. Yeh, T.C.; Niu, D.M.; Cheng, H.C.; Chen, Y.R.; Chen, L.Z.; Tsui, S.P.; Liao, T.W.E.; Wang, A.G.; Yang, C.F. Novel Mutation of IFT140 in an Infant with Mainzer-Saldino Syndrome Presenting with Retinal Dystrophy. Mol. Genet. Metab. Rep. 2022, 33, 100937.

  4. Perrault, I.; Saunier, S.; Hanein, S.; Filhol, E.; Bizet, A.A.; Collins, F.; Salih, M.A.M.; Gerber, S.; Delphin, N.; Bigot, K.; et al. Mainzer-Saldino Syndrome Is a Ciliopathy Caused by IFT140 Mutations. Am. J. Hum. Genet. 2012, 90, 864–870.

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  6. Walczak-Sztulpa, J.; Posmyk, R.; Bukowska-Olech, E.M.; Wawrocka, A.; Jamsheer, A.; Oud, M.M.; Schmidts, M.; Arts, H.H.; Latos-Bielenska, A.; Wasilewska, A. Compound Heterozygous IFT140 Variants in Two Polish Families with Sensenbrenner Syndrome and Early Onset End-Stage Renal Disease. Orphanet J. Rare Dis. 2020, 15, 36.

  7. Bayat, A.; Kerr, B.; Douzgou, S. The Evolving Craniofacial Phenotype of a Patient with Sensenbrenner Syndrome Caused by IFT140 Compound Heterozygous Mutations. Clin. Dysmorphol. 2017, 26, 247–251.

  8. Walczak-Sztulpa, J.; Wawrocka, A.; Doornbos, C.; van Beek, R.; Sowińska-Seidler, A.; Jamsheer, A.; Bukowska-Olech, E.; Latos-Bieleńska, A.; Grenda, R.; Bongers, E.M.H.F.; et al. Identical IFT140 Variants Cause Variable Skeletal Ciliopathy Phenotypes—Challenges for the Accurate Diagnosis. Front. Genet. 2022, 13, 931822.

  9. Zaffanello, M.; Diomedi-Camassei, F.; Melzi, M.L.; Torre, G.; Callea, F.; Emma, F. Sensenbrenner Syndrome: A New Member of the Hepatorenal Fibrocystic Family. Am. J. Hum. Genet. 2006, 221, 212–221.

  10. Handa, A.; Voss, U.; Hammarsjö, A.; Grigelioniene, G.; Nishimura, G. Skeletal Ciliopathies: A Pattern Recognition Approach. Jpn. J. Radiol. 2020, 38, 193–206.

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