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  • 1
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    Intrafamilial phenotypic variability in a Polish family with Sensenbrenner syndrome and biallelic WDR35 mutations
    Wiley ; 2017
    In:  American Journal of Medical Genetics Part A Vol. 173, No. 5 ( 2017-05), p. 1364-1368
    Details
    In: American Journal of Medical Genetics Part A, Wiley, Vol. 173, No. 5 ( 2017-05), p. 1364-1368
    Abstract: Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy. Cranioectodermal dysplasia is characterized by craniofacial, skeletal, and ectodermal abnormalities. About 50 patients have been described to date. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disorder. Mutations in five genes: IFT122, WDR35, IFT43, WDR19 , and IFT52 have been associated with CED. All known genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. Here, we report a family with two children affected by Sensenbrenner syndrome, a 9‐year‐old girl and her older sister who died in infancy due to respiratory, liver, and renal insufficiency. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, preaxial polydactyly of left hand, narrow chest, craniosynostosis, dolichocephaly, high anterior hairline, epicanthal folds and telecanthus, depressed nasal bridge, low‐set ears, and additional ectodermal abnormalities. The patient presented with chronic tubulointerstitial renal disease. She had abnormal echogenicity on renal ultrasound, reduced glomerular filtration, albuminuria and tubular proteinuria, hypocalciuria and hypocitraturia, accompanied by pre‐hypertensive state. This pattern of renal abnormality was regarded as nephronophthisis. Psychomotor development was apparently normal. Molecular analysis in one of the affected individuals identified compound heterozygosity for a nonsense (c.1922T 〉 G, p.(Leu641*)) and missense (c.2522A 〉 T, p.(Asp841Val)) variants in WDR35 . We present a detailed clinical descriptions of two female siblings showing an intrafamilial phenotypic variability of the disease, and illustrating the potential lethality of CED.
    Type of Medium: Online Resource
    ISSN: 1552-4825 , 1552-4833
    URL: Issue
    URL: Article
    DOI: 10.1002/ajmg.a.v173.5
    DOI: 10.1002/ajmg.a.38163
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 1493479-6
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  • 2
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    Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease
    Springer Science and Business Media LLC ; 2020
    In:  Orphanet Journal of Rare Diseases Vol. 15, No. 1 ( 2020-12)
    Details
    In: Orphanet Journal of Rare Diseases, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2020-12)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1750-1172
    URL: Article
    DOI: 10.1186/s13023-020-1303-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2225857-7
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  • 3
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    Molecular background of Leber congenital amaurosis in a Polish cohort of patients—novel variants discovered by NGS
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Applied Genetics Vol. 64, No. 1 ( 2023-02), p. 89-104
    Details
    In: Journal of Applied Genetics, Springer Science and Business Media LLC, Vol. 64, No. 1 ( 2023-02), p. 89-104
    Abstract: Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophies and the most frequent cause of congenital blindness in children. To date, 25 genes have been implicated in the pathogenesis of this rare disorder. Performing an accurate molecular diagnosis is crucial as gene therapy is becoming available. This study aimed to report the molecular basis of Leber congenital amaurosis, especially novel and rare variants in 27 Polish families with a clinical diagnosis of LCA fully confirmed by molecular analyses. Whole exome sequencing or targeted next-generation sequencing (NGS) of inherited retinal dystrophies-associated (IRD) genes was applied to identify potentially pathogenic variants. Bidirectional Sanger sequencing and quantitative PCR (qPCR) were carried out for validation and segregation analysis of the variants identified within the families. We identified 28 potentially pathogenic variants, including 11 novel, in 8 LCA genes: CEP290 , CRB1 , GUCY2D , NMNAT1 , RPGRIP1 , CRX , LRAT1 , and LCA5. This study expands the mutational spectrum of the LCA genes. Moreover, these results, together with the conclusions from our previous studies, allow us to point to the most frequently mutated genes and variants in the Polish cohort of LCA patients.
    Type of Medium: Online Resource
    ISSN: 1234-1983 , 2190-3883
    URL: Article
    DOI: 10.1007/s13353-022-00733-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2194407-6
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  • 4
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    DataSheet1.docx
    Frontiers Media SA ; 2022
    In:  Frontiers in Genetics Vol. 13 ( 2022-7-7)
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    In: Frontiers in Genetics, Frontiers Media SA, Vol. 13 ( 2022-7-7)
    Abstract: Ciliopathies are rare congenital disorders, caused by defects in the cilium, that cover a broad clinical spectrum. A subgroup of ciliopathies showing significant phenotypic overlap are known as skeletal ciliopathies and include Jeune asphyxiating thoracic dysplasia (JATD), Mainzer-Saldino syndrome (MZSDS), cranioectodermal dysplasia (CED), and short-rib polydactyly (SRP). Ciliopathies are heterogeneous disorders with & gt;187 associated genes, of which some genes are described to cause more than one ciliopathy phenotype. Both the clinical and molecular overlap make accurate diagnosing of these disorders challenging. We describe two unrelated Polish patients presenting with a skeletal ciliopathy who share the same compound heterozygous variants in IFT140 (NM_014,714.4) r.2765_2768del; p.(Tyr923Leufs*28) and exon 27–30 duplication; p.(Tyr1152_Thr1394dup). Apart from overlapping clinical symptoms the patients also show phenotypic differences; patient 1 showed more resemblance to a Mainzer-Saldino syndrome (MZSDS) phenotype, while patient 2 was more similar to the phenotype of cranioectodermal dysplasia (CED). In addition, functional testing in patient-derived fibroblasts revealed a distinct cilium phenotyps for each patient, and strikingly, the cilium phenotype of CED-like patient 2 resembled that of known CED patients. Besides two variants in IFT140 , in depth exome analysis of ciliopathy associated genes revealed a likely-pathogenic heterozygous variant in INTU for patient 2 that possibly affects the same IFT-A complex to which IFT140 belongs and thereby could add to the phenotype of patient 2. Taken together, by combining genetic data, functional test results, and clinical findings we were able to accurately diagnose patient 1 with “IFT140-related ciliopathy with MZSDS-like features” and patient 2 with “IFT140-related ciliopathy with CED-like features”. This study emphasizes that identical variants in one ciliopathy associated gene can lead to a variable ciliopathy phenotype and that an in depth and integrated analysis of clinical, molecular and functional data is necessary to accurately diagnose ciliopathy patients.
    Type of Medium: Online Resource
    ISSN: 1664-8021
    URL: Article
    URL: Article
    DOI: 10.3389/fgene.2022.931822
    DOI: 10.3389/fgene.2022.931822.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606823-0
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  • 5
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    Clinical and molecular genetic characterization of a male patient with Sensenbrenner syndrome (cranioectodermal dysplasia) and biallelic WDR35 mutations
    Wiley ; 2018
    In:  Birth Defects Research Vol. 110, No. 4 ( 2018-03), p. 376-381
    Details
    In: Birth Defects Research, Wiley, Vol. 110, No. 4 ( 2018-03), p. 376-381
    Abstract: Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy first described by Judith Sensenbrenner in 1975. CED is a complex disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. The clinical symptoms are variable and the CED phenotype may present intrafamilial and interfamilial differences. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disease. Mutations in six genes: IFT122, WDR35, IFT43, WDR19, IFT52 , and IFT140 have been associated with this disorder. All known CED genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. Case We report a on 2‐year‐old male patient affected by Sensenbrenner syndrome. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, narrow chest, high forehead, epicanthal folds, telecanthus, broad nasal bridge, low‐set ears, sparse hair, and widely space teeth. Craniosynostosis was surgically corrected at the age of 4 months. The patient presented chronic renal disease. Nephrologic picture showed early stages of nephronophthisis. Psychomotor development was apparently normal. Molecular analysis of the affected individual revealed compound heterozygosity for a novel nonsense p.(Arg113*) and a missense p.(Asp841Val) variant in the WDR35 gene. Conclusions The observations of the CED patient in this study provide additional clinical data and expand the molecular spectrum of Sensenbrenner syndrome. Moreover, the two variants identified in the proband provide further evidence for the WDR35 mutations as the most common cause of this rare syndrome.
    Type of Medium: Online Resource
    ISSN: 2472-1727 , 2472-1727
    URL: Issue
    URL: Article
    DOI: 10.1002/bdr2.v110.4
    DOI: 10.1002/bdr2.1151
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2884154-2
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  • 6
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    WDR35 variants in a cranioectodermal dysplasia patient with early onset end‐stage renal disease and retinal dystrophy
    Wiley ; 2022
    In:  American Journal of Medical Genetics Part A Vol. 188, No. 10 ( 2022-10), p. 3071-3077
    Details
    In: American Journal of Medical Genetics Part A, Wiley, Vol. 188, No. 10 ( 2022-10), p. 3071-3077
    Abstract: Cranioectodermal dysplasia (CED) is rare heterogeneous condition. It belongs to a group of disorders defined as ciliopathies and is associated with defective cilia function and structure. To date six genes have been associated with CED. Here we describe a 4‐year‐old male CED patient whose features include dolichocephaly, multi‐suture craniosynostosis, epicanthus, frontal bossing, narrow thorax, limb shortening, and brachydactyly. The patient presented early‐onset chronic kidney disease and was transplanted at the age of 2 years and 5 months. At the age of 3.5 years a retinal degeneration was diagnosed. Targeted sequencing by NGS revealed the presence of compound heterozygous variants in the WDR35 gene. The variants are a novel missense change in exon 9 p.(Gly303Arg) and a previously described nonsense variant in exon 18 p.(Leu641*). Our findings suggest that patients with WDR35 defects may be at risk to develop early‐onset retinal degeneration. Therefore, CED patients with pathogenic variation in this gene should be assessed at least once by the ophthalmologist before the age of 4 years to detect early signs of retinal degeneration.
    Type of Medium: Online Resource
    ISSN: 1552-4825 , 1552-4833
    URL: Issue
    URL: Article
    DOI: 10.1002/ajmg.a.v188.10
    DOI: 10.1002/ajmg.a.62903
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1493479-6
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  • 7
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    Molecular Re-Diagnosis with Whole-Exome Sequencing Increases the Diagnostic Yield in Patients with Non-Syndromic Retinitis Pigmentosa
    MDPI AG ; 2023
    In:  Diagnostics Vol. 13, No. 4 ( 2023-02-14), p. 730-
    Details
    In: Diagnostics, MDPI AG, Vol. 13, No. 4 ( 2023-02-14), p. 730-
    Abstract: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of disorders with progressive loss of photoreceptor and pigment epithelial function. Nineteen unrelated Polish probands clinically diagnosed with nonsyndromic RP were recruited to this study. We used whole-exome sequencing (WES) to identify potential pathogenic gene variants in molecularly undiagnosed RP patients, as a molecular re-diagnosis after having performed targeted NGS in the past. Targeted NGS allowed for identification of the molecular background in only 5 out of 19 patients. Fourteen patients who remained unsolved despite the targeted NGS were subjected to WES. WES revealed potentially causative variants in RP-related genes in another 12 patients. Together, NGS methods revealed the coexistence of causal variants affecting distinct RP genes in 17 out of 19 RP families, with a very high efficiency of 89%. With the improvement of NGS methods, including higher sequencing depth, broader target enrichment, and better bioinformatic analysis capabilities, the ratio of identified causal gene variants has significantly increased. Therefore, it is important to consider repeating high-throughput sequencing analysis in those patients in whom the previously performed NGS did not reveal any pathogenic variants. The study confirmed the efficiency and clinical utility of re-diagnosis with WES in molecularly undiagnosed RP patients.
    Type of Medium: Online Resource
    ISSN: 2075-4418
    URL: Article
    DOI: 10.3390/diagnostics13040730
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2662336-5
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  • 8
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    Non‐syndromic anophthalmia/microphthalmia can be caused by a PORCN variant inherited in X‐linked recessive manner
    Wiley ; 2021
    In:  American Journal of Medical Genetics Part A Vol. 185, No. 1 ( 2021-01), p. 250-255
    Details
    In: American Journal of Medical Genetics Part A, Wiley, Vol. 185, No. 1 ( 2021-01), p. 250-255
    Abstract: Anophthalmia and microphthalmia (A/M) represent severe developmental ocular malformations, corresponding, respectively, to absent eyeball or reduced size of the eye. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome. Genetic heterogeneity has been demonstrated, and many genes have been reported to be associated with A/M. The advances in high‐throughput sequencing have proven highly effective in defining the molecular basis of A/M. Nevertheless, there are still many patients with unsolved genetic background of the disease, who pose a significant challenge in the molecular diagnostics of A/M. Here we describe a family, with three males affected with the non‐syndromic A/M. Whole exome‐sequencing performed in Patient 1, revealed the presence of a novel probably pathogenic variant c.734A 〉 G, (p.[Tyr245Cys]) in the PORCN gene. Pedigree analysis and segregation of the identified variant in the family confirmed the X‐linked recessive pattern of inheritance. This is the first report of X‐linked recessive non‐syndromic A/M. Until now, pathogenic variants in the PORCN gene have been identified in the patients with Goltz syndrome, but they were inherited in X‐linked dominant mode. The ocular phenotype is the only finding observed in the patients, which allows to exclude the diagnosis of Goltz syndrome.
    Type of Medium: Online Resource
    ISSN: 1552-4825 , 1552-4833
    URL: Issue
    URL: Article
    DOI: 10.1002/ajmg.a.v185.1
    DOI: 10.1002/ajmg.a.61938
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 1493479-6
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  • 9
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    Prenatal genetic diagnosis of cranioectodermal dysplasia in a Polish family with compound heterozygous variants in WDR35
    Wiley ; 2020
    In:  American Journal of Medical Genetics Part A Vol. 182, No. 10 ( 2020-10), p. 2417-2425
    Details
    In: American Journal of Medical Genetics Part A, Wiley, Vol. 182, No. 10 ( 2020-10), p. 2417-2425
    Abstract: The ciliary chondrodysplasias represent a group of clinically and genetically heterogeneous disorders that affect skeleton development. Cilia are organelles that project from the surface of many cell types and play an important role during prenatal and postnatal human development. Cranioectodermal dysplasia (Sensenbrenner syndrome, CED) is a ciliopathy primarily characterized by craniofacial, skeletal, and ectodermal abnormalities. To date six genes have been associated with CED: IFT122 , WDR35 , WDR19 , IFT140 , IFT43 , and IFT52 . Prenatal diagnosis of CED is challenging, and genetic testing can facilitate making a correct diagnosis. Here, we report on a family with two male siblings affected by CED: a 3.5 year‐old patient and his 2 year‐old brother. Molecular analysis of the proband at 1 year of age revealed compound heterozygous variants in WDR35 : c.3G 〉 A [p.(Met1‐Ala30delinsMetfsTer4)] and c.2522A 〉 T [p.(Asp841Val)]. Ultrasound examination during the second pregnancy revealed an increased nuchal translucency of 4.5 mm and a hypoplastic nasal bone at 12 weeks of gestation. Prenatal diagnostic testing was offered because of an increased risk for chromosomal abnormalities and recurrence risk for CED. Prenatal genetic analysis of a chorionic villus sample detected the WDR35 variants previously identified in the elder brother. This is the first report of a prenatal genetic diagnosis in CED.
    Type of Medium: Online Resource
    ISSN: 1552-4825 , 1552-4833
    URL: Issue
    URL: Article
    DOI: 10.1002/ajmg.a.v182.10
    DOI: 10.1002/ajmg.a.61785
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 1493479-6
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  • 10
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    Interfamilial clinical variability in four Polish families with cranioectodermal dysplasia and identical compound heterozygous variants in WDR35
    Wiley ; 2021
    In:  American Journal of Medical Genetics Part A Vol. 185, No. 4 ( 2021-04), p. 1195-1203
    Details
    In: American Journal of Medical Genetics Part A, Wiley, Vol. 185, No. 4 ( 2021-04), p. 1195-1203
    Abstract: Cranioectodermal dysplasia (CED) is a rare autosomal recessive disorder primarily characterized by craniofacial, skeletal, and ectodermal abnormalities. CED is a chondrodysplasia, which is part of a spectrum of clinically and genetically heterogeneous diseases that result from disruptions in cilia. Pathogenic variants in genes encoding components of the ciliary transport machinery are known to cause CED. Intra‐ and interfamilial clinical variability has been reported in a few CED studies and the findings of this study align with these observations. Here, we report on five CED patients from four Polish families with identical compound heterozygous variants [c.1922T 〉 G p.(Leu641Ter) and c.2522A 〉 T; p.(Asp841Val)] in WDR35 . The frequent occurrence of both identified changes in Polish CED families suggests that these variants may be founder mutations. Clinical evaluation of the CED patients revealed interfamilial clinical variability among the patients. This includes differences in skeletal and ectodermal features as well as variability in development, progression, and severity of renal and liver insufficiency. This is the first report showing significant interfamilial clinical variability in a series of CED patients from unrelated families with identical compound heterozygous variants in WDR35 . Our findings strongly indicate that other genetic and non‐genetic factors may modulate the progression and expression of the patients' phenotypes.
    Type of Medium: Online Resource
    ISSN: 1552-4825 , 1552-4833
    URL: Issue
    URL: Article
    DOI: 10.1002/ajmg.a.v185.4
    DOI: 10.1002/ajmg.a.62067
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 1493479-6
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