Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease
Abstract Background Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and rena...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-02-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-020-1303-2 |
| _version_ | 1818854951984562176 |
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| author | Joanna Walczak-Sztulpa Renata Posmyk Ewelina M. Bukowska-Olech Anna Wawrocka Aleksander Jamsheer Machteld M. Oud Miriam Schmidts Heleen H. Arts Anna Latos-Bielenska Anna Wasilewska |
| author_facet | Joanna Walczak-Sztulpa Renata Posmyk Ewelina M. Bukowska-Olech Anna Wawrocka Aleksander Jamsheer Machteld M. Oud Miriam Schmidts Heleen H. Arts Anna Latos-Bielenska Anna Wasilewska |
| author_sort | Joanna Walczak-Sztulpa |
| collection | DOAJ |
| description | Abstract Background Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects. Results Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. Conclusion The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients. |
| first_indexed | 2024-12-19T08:00:52Z |
| format | Article |
| id | doaj.art-3a057c1244e44416b324608e85beb311 |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-19T08:00:52Z |
| publishDate | 2020-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-3a057c1244e44416b324608e85beb3112022-12-21T20:29:53ZengBMCOrphanet Journal of Rare Diseases1750-11722020-02-0115111010.1186/s13023-020-1303-2Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal diseaseJoanna Walczak-Sztulpa0Renata Posmyk1Ewelina M. Bukowska-Olech2Anna Wawrocka3Aleksander Jamsheer4Machteld M. Oud5Miriam Schmidts6Heleen H. Arts7Anna Latos-Bielenska8Anna Wasilewska9Department of Medical Genetics, Poznan University of Medical SciencesDepartment of Perinatology, Medical University of BialystokDepartment of Medical Genetics, Poznan University of Medical SciencesDepartment of Medical Genetics, Poznan University of Medical SciencesDepartment of Medical Genetics, Poznan University of Medical SciencesDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Pathology and Laboratory Medicine, Dalhousie UniversityDepartment of Medical Genetics, Poznan University of Medical SciencesDepartment of Pediatrics and Nephrology, Medical University of BialystokAbstract Background Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects. Results Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. Conclusion The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.https://doi.org/10.1186/s13023-020-1303-2Sensenbrenner syndromeCranioectodermal dysplasiaIFT140CiliopathyEnd-stage renal disease |
| spellingShingle | Joanna Walczak-Sztulpa Renata Posmyk Ewelina M. Bukowska-Olech Anna Wawrocka Aleksander Jamsheer Machteld M. Oud Miriam Schmidts Heleen H. Arts Anna Latos-Bielenska Anna Wasilewska Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease Orphanet Journal of Rare Diseases Sensenbrenner syndrome Cranioectodermal dysplasia IFT140 Ciliopathy End-stage renal disease |
| title | Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease |
| title_full | Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease |
| title_fullStr | Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease |
| title_full_unstemmed | Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease |
| title_short | Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease |
| title_sort | compound heterozygous ift140 variants in two polish families with sensenbrenner syndrome and early onset end stage renal disease |
| topic | Sensenbrenner syndrome Cranioectodermal dysplasia IFT140 Ciliopathy End-stage renal disease |
| url | https://doi.org/10.1186/s13023-020-1303-2 |
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