Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease

Autor: Ewelina Bukowska-Olech, Aleksander Jamsheer, Machteld M. Oud, Anna Wasilewska, Heleen H. Arts, Anna Wawrocka, Anna Latos-Bielenska, Joanna Walczak-Sztulpa, Renata Posmyk, Miriam Schmidts
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
Sensenbrenner syndrome
Ciliopathy
lcsh:Medicine
Gene mutation
Compound heterozygosity
Bioinformatics
Bone and Bones
End stage renal disease
Cranioectodermal dysplasia
Craniosynostoses
03 medical and health sciences
End-stage renal disease
All institutes and research themes of the Radboud University Medical Center
Ectodermal Dysplasia
IFT140
medicine
Humans
Pharmacology (medical)
Genetics (clinical)
Exome sequencing
030304 developmental biology
0303 health sciences
business.industry
Genetic heterogeneity
Research
030305 genetics & heredity
lcsh:R
General Medicine
medicine.disease
Cilium assembly
3. Good health
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]
Child
Preschool
Mutation
Kidney Failure
Chronic
Poland
Carrier Proteins
business
Cranioectodermal Dysplasia
Zdroj: Orphanet Journal of Rare Diseases, Vol 15, Iss 1, Pp 1-10 (2020)
Orphanet Journal of Rare Diseases, 15
Orphanet Journal of Rare Diseases, 15, 1
Orphanet Journal of Rare Diseases
ISSN: 1750-1172
Popis: 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.
Databáze: OpenAIRE
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