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

Walczak‐Sztulpa, Joanna; Posmyk, Renata; Bukowska‐Olech, Ewelina; Wawrocka, Anna; Jamsheer, Aleksander; Oud, Machteld M.; Schmidts, Miriam; Arts, Heleen H.; Latos‐Bieleńska, Anna; Wasilewska, Anna

doi:10.1186/s13023-020-1303-2

Cited by 13 publications

(16 citation statements)

References 23 publications

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“…The deletion variant in IFT140 r.2765_2768 has previously been reported as a likely pathogenic variant in ClinVar (VCV000863072.3) in a patient with retinal dystrophy, as well as, a patient with MZSDS. The duplication variant in IFT140 NC_000016.9:g.1568118(NM_014714.4):c (4182 + 99)_(3558)dup is absent from ClinVar, but has been detected in two Polish skeletal ciliopathy patients and in eight families reported by Geoffroy ( Geoffroy et al, 2018 ; Walczak-Sztulpa et al, 2020 ). These include six families (seven patients) diagnosed with MZSDS, one patient with JATD and one affected individual with features of CED.…”

Section: Resultsmentioning

confidence: 99%

“…-Congenital CMV infection -Epilepsy (absence attacks) from the age of 13 years, treated with Valproate -MRI -normal a -IFT140-related MZSDS, phenotype based on literature (Perrault et al, 2012;Schmidts et al, 2013;Geoffroy et al, 2018;Oud et al, 2018); b -IFT140-related CED, phenotype based on literature (Bayat et al, 2017;Walczak-Sztulpa et al, 2020); c -CED, phenotype based on literature, excluding IFT140 (Gilissen et al, 2010;Walczak-Sztulpa et al, 2010;Arts et al, 2011;Bredrup et al, 2011); CT, computed tomography; EEG, electroencephalography; ID, intellectual disability; Mat, maternally inherited variant; MRI, magnetic resonance imaging; NA, data not available; Pat, paternally inherited variant; WG, weeks of gestation. + feature present;-feature absent; *presence, number of renal cysts, revealed by repeated ultrasonography not seen at baseline, has increased over time of follow-up; # unclear.…”

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confidence: 99%

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Identical IFT140 Variants Cause Variable Skeletal Ciliopathy Phenotypes—Challenges for the Accurate Diagnosis

et al. 2022

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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 >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.

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Section: Resultsmentioning

confidence: 99%

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Identical IFT140 Variants Cause Variable Skeletal Ciliopathy Phenotypes—Challenges for the Accurate Diagnosis

et al. 2022

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“…Using a cilium dual reporter-expressing mouse model, we found that a small group of hepatocytes were ciliated. Among ciliopathies, liver cysts and fibrosis are common pathological changes, suggesting that primary cilia are essential to the normal function of the liver [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Cilia in Different Mouse Tissues

Yang

Deepak

et al. 2021

Cells

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Cilia are microtubule-based hair-like organelles that extend from the cell surface. However, the existence and distribution of cilia in each organ and tissue at the postnatal stage in vivo remain largely unknown. In this study, we defined cilia distribution and arrangement and measured the ciliary lengths and the percentage of ciliated cells in different organs and tissues in vivo by using cilium dual reporter-expressing transgenic mice. Cilia were identified by the presence of ARL13B with an mCherry+ signal, and the cilium basal body was identified by the presence of Centrin2 with a GFP+ signal. Here, we provide in vivo evidence that chondrocytes and cells throughout bones have cilia. Most importantly, we reveal that: 1. primary cilia are present in hepatocytes; 2. no cilia but many centrioles are distributed on the apical cell surface in the gallbladder, intestine, and thyroid epithelia; 3. cilia on the cerebral cortex are well oriented, pointing to the center of the brain; 4. ARL13B+ inclusion is evident in the thyroid and islets of Langerhans; and 5. approximately 2% of cilia show irregular movement in nucleus pulposus extracellular fluid. This study reveals the existence and distribution of cilia and centrioles in different tissues and organs, and provides new insights for further comprehensive study of ciliary function in these organs and tissues.

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“…We applied qPCR to determine the 17p13.3 locus dosage and narrow down its genomic coordinates using SYBR dye-based master mix (SYBR Green PCR Master Mix; ThermoFisher Scientific). Reactions ran on the Viia7 cycler as described previously [ 25 ]. In short, we applied the comparative 2 −ΔΔCT method using control DNA as a calibrator.…”

Section: Methodsmentioning

confidence: 99%

SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably

Bukowska‐Olech

Sowińska‐Seidler

Wierzba

et al. 2022

Orphanet J Rare Dis

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Background Split-hand/ foot malformation with long bone deficiency 3 (SHFLD3) is an extremely rare condition associated with duplications located on 17p13.3, which invariably encompasses the BHLHA9 gene. The disease inherits with variable expressivity and significant incomplete penetrance as high as 50%. Results We have detected 17p13.3 locus one-allele triplication in a male proband from family 1 (F1.1), and duplication in a male proband from family 2 (F2.1) applying array comparative genomic hybridization (array CGH). The rearrangements mapped to the following chromosomal regions–arr[GRCh38] 17p13.3(960254–1291856)×4 in F1.1 and arr[GRCh38] 17p13.3(1227482–1302716)×3 in F2.1. The targeted quantitative PCR revealed that the 17p13.3 locus was also duplicated in the second affected member from family 2 (F2.2; brother of F2.1). In the next step, we performed segregation studies using quantitative PCR and revealed that F1.1 inherited the triplication from his healthy father—F1.2, whereas the locus was unremarkable in the mother of F2.1 & F2.2 and the healthy son of F2.1. However, the duplication was present in a healthy daughter of F2.2, an asymptomatic carrier. The breakpoint analysis allowed to define the exact size and span of the duplicated region in Family 2, i.e., 78,948 bp chr17:1225063–1304010 (HG38). Interestingly, all symptomatic carriers from both families presented with variable SHFLD3 phenotype. The involvement of secondary modifying locus could not be excluded, however, the Sanger sequencing screening of BHLHA9 entire coding sequence was unremarkable for both families. Conclusions We have shed light on the one-allele CNV triplication occurrence that should be considered when a higher probe (over duplication range) signal is noted. Second, all SHFLD3 patients were accurately described regarding infrequent limb phenotypes, which were highly variable even when familial. Of note, all symptomatic individuals were males. SHFLD3 still remains a mysterious ultra-rare disease and our findings do not answer crucial questions regarding the disease low penetrance, variable expression and heterogeneity. However, we have presented some clinical and molecular aspects that may be helpful in daily diagnostic routine, both dysmorphological and molecular assessment, of patients affected with SHFLD3.

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

Cited by 13 publications

References 23 publications

Identical IFT140 Variants Cause Variable Skeletal Ciliopathy Phenotypes—Challenges for the Accurate Diagnosis

Identical IFT140 Variants Cause Variable Skeletal Ciliopathy Phenotypes—Challenges for the Accurate Diagnosis

Identification of Cilia in Different Mouse Tissues

SHFLD3 phenotypes caused by 17p13.3 triplication/ duplication encompassing Fingerin (BHLHA9) invariably

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