ClinVar Genomic variation as it relates to human health

Short-Rib Thoracic Dysplasia 9 In a 17-year-old boy with short-rib thoracic dysplasia-9 (SRTD9; 266920) with a clinical diagnosis of Mainzer-Saldino syndrome, who exhibited a small thoracic cavity with short and thick ribs and had early-onset retinal dystrophy and chronic renal failure, Perrault et al. (2012) identified compound heterozygosity for 2 mutations in the IFT140 gene: a 1990G-A transition, resulting in a glu664-to-lys (E664K) substitution at a highly conserved residue, and a G-to-T transversion in intron 19 (2399+1G-T; 614620.0002), predicted to result in the skipping of exon 18. The mutations were detected by ciliome sequencing of the patient's DNA and confirmed by Sanger sequencing; they were not found in 200 control chromosomes. Five affected individuals from 2 additional consanguineous Saudi Arabian families with a clinical diagnosis of Mainzer-Saldino syndrome were found to be homozygous for the E664K mutation. In vitro functional expression studies in retinal pigment epithelial cells demonstrated that the mutant protein had partial to complete loss of basal body localization and an increase of cytoplasmic staining, indicating severe disorganization. Patient fibroblasts showed absent cilia in a high proportion of cells compared to controls, consistent with a defect in ciliogenesis and/or cilia maintenance. Although mutant IFT140 was localized along the cilia axoneme, there appeared to be a defect in retrograde ciliary transport with an abnormal distribution of other ciliary proteins. All patients had onset of retinal dystrophy in infancy with visual loss and nystagmus, and all exhibited skeletal anomalies, including short stature in most, phalangeal cone-shaped epiphyses, and metaphyseal defects in the hips (in 3). In contrast to the compound heterozygous patient, none of the Saudi Arabian patients had overt renal disease and their thorax phenotype was reported to be unremarkable. Four of the 5 Saudi Arabian patients had mild intellectual disability or autistic features with seizures, which may have been due to other factors. Retinitis Pigmentosa 80 In 10 Saudi probands with congenital severe retinopathy (RP80; 617781), including 2 boys previously reported by Khan et al. (2014), Bifari et al. (2016) identified homozygosity for the E664K substitution (c.1990G-A, NM_014714.3) in the IFT140 gene. Some patients exhibited additional features, including developmental delay in 7 of the patients, and cone-shaped phalangeal epiphyses in the 5 who underwent hand x-rays. Noting that all but 1 of the families they studied harbored the E664K mutation, the authors suggested that this represented a founder effect or a mutation hotspot. (less)

Short-Rib Thoracic Dysplasia 9 In a 17-year-old boy with short-rib thoracic dysplasia-9 (SRTD9; 266920) with a clinical diagnosis of Mainzer-Saldino syndrome, who exhibited a small thoracic cavity with short and thick ribs and had early-onset retinal dystrophy and chronic renal failure, Perrault et al. (2012) identified compound heterozygosity for 2 mutations in the IFT140 gene: a 1990G-A transition, resulting in a glu664-to-lys (E664K) substitution at a highly conserved residue, and a G-to-T transversion in intron 19 (2399+1G-T; 614620.0002), predicted to result in the skipping of exon 18. The mutations were detected by ciliome sequencing of the patient's DNA and confirmed by Sanger sequencing; they were not found in 200 control chromosomes. Five affected individuals from 2 additional consanguineous Saudi Arabian families with a clinical diagnosis of Mainzer-Saldino syndrome were found to be homozygous for the E664K mutation. In vitro functional expression studies in retinal pigment epithelial cells demonstrated that the mutant protein had partial to complete loss of basal body localization and an increase of cytoplasmic staining, indicating severe disorganization. Patient fibroblasts showed absent cilia in a high proportion of cells compared to controls, consistent with a defect in ciliogenesis and/or cilia maintenance. Although mutant IFT140 was localized along the cilia axoneme, there appeared to be a defect in retrograde ciliary transport with an abnormal distribution of other ciliary proteins. All patients had onset of retinal dystrophy in infancy with visual loss and nystagmus, and all exhibited skeletal anomalies, including short stature in most, phalangeal cone-shaped epiphyses, and metaphyseal defects in the hips (in 3). In contrast to the compound heterozygous patient, none of the Saudi Arabian patients had overt renal disease and their thorax phenotype was reported to be unremarkable. Four of the 5 Saudi Arabian patients had mild intellectual disability or autistic features with seizures, which may have been due to other factors. Retinitis Pigmentosa 80 In 10 Saudi probands with congenital severe retinopathy (RP80; 617781), including 2 boys previously reported by Khan et al. (2014), Bifari et al. (2016) identified homozygosity for the E664K substitution (c.1990G-A, NM_014714.3) in the IFT140 gene. Some patients exhibited additional features, including developmental delay in 7 of the patients, and cone-shaped phalangeal epiphyses in the 5 who underwent hand x-rays. Noting that all but 1 of the families they studied harbored the E664K mutation, the authors suggested that this represented a founder effect or a mutation hotspot. (less)