Abstract
BackgroundMainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses.MethodsWe performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived Ift140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry.ResultsDiagnostic WES revealed two novel compound heterozygous variants in IFT140, encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived Ift140 knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct.ConclusionsBy combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer–Saldino syndrome, caused by variants in IFT140. We suggest the possibility that variants in IFT140 may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing.
Highlights
Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders
Short-rib thoracic dysplasia (SRTD) refers to a group of ciliopathies characterized by skeletal abnormalities, that are classified into 18 molecular subclasses; SRTD1-16, Ellis-van Creveld (EVC), and EVC2
Monitoring renal function is likely to be more important for patients carrying a pathogenic variant in IFT140, TTC21B, or WDR19 than for patients who carry DYNC2H1 or IFT80 variants, as the latter two are primarily associated with a skeletal phenotype and IFT140, TTC21B, and WDR19 are associated with a skeletal phenotype accompanied by renal insufficiency and retinal degeneration [2, 10]
Summary
Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. Variants in two genes are associated with MZSDS: IFT140, and IFT172. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. Short-rib thoracic dysplasia (SRTD) refers to a group of ciliopathies characterized by skeletal abnormalities, that are classified into 18 molecular subclasses; SRTD1-16, EVC, and EVC2. Variants in genes encoding subunits of the IFT-A particle are associated with SRTD types 3–5, 7–9, 11, and 15 [1, 2, 4, 5, 8]. The characteristic skeletal findings of SRTDs comprise short ribs and a narrow thorax and are often combined with short stature, pelvic deformities, polydactyly, and brachydactyly. Monitoring renal function is likely to be more important for patients carrying a pathogenic variant in IFT140, TTC21B, or WDR19 than for patients who carry DYNC2H1 or IFT80 variants, as the latter two are primarily associated with a skeletal phenotype and IFT140, TTC21B, and WDR19 are associated with a skeletal phenotype accompanied by renal insufficiency and retinal degeneration [2, 10]
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