ClinVar Genomic variation as it relates to human health

In 2 affected members of a family with short-rib thoracic dysplasia-9 without polydactyly (SRTD9; 266920), who had a clinical diagnosis of Mainzer-Saldino syndrome, Perrault et al. (2012) identified compound heterozygosity for 2 mutations in the IFT140 gene: a c.634G-A transition resulting in a gly212-to-arg (G212R) substitution, and a 1-bp duplication (c.3916dup; 614620.0006), resulting in a frameshift and premature termination (Ala1306GlyfsTer56). Neither mutation was found in 200 control chromosomes and both were predicted to be deleterious. In vitro functional expression studies in retinal pigment epithelial cells demonstrated that the G212R mutant protein had partial to complete loss of basal body localization and an increase of cytoplasmic staining. The patients had early-onset retinitis pigmentosa with poor visual acuity, chronic renal failure leading to end-stage renal disease, and cholestasis. The kidneys were hyperechogenic with loss of corticomedullary differentiation. Both also had skeletal anomalies, including short stature, craniosynostosis, and phalangeal cone-shaped epiphyses. Psychomotor development was normal at ages 4 and 10 years, respectively. Perrault et al. (2012) also identified compound heterozygosity for the G212R mutation and a splice site mutation in the IFT140 gene (614620.0002) in an 18-month-old boy with a clinical diagnosis of Jeune syndrome, who exhibited short thorax with short ribs and trident-shaped spurs on long bones. In a 6.5-year-old British boy with short stature, short ribs and narrow thorax, retinal dystrophy, and end-stage renal failure, who also exhibited brachydactyly and ectodermal features and received a clinical diagnosis of Sensenbrenner syndrome (see 218330), Bayat et al. (2017) identified compound heterozygosity for the G212R mutation and a c.2278C-T transition in the IFT140 gene, resulting in an arg760-to-ter (R760X; 614620.0016) substitution. His unaffected parents were each heterozygous for 1 of the mutations. In a 10-year-old boy with features of Mainzer-Saldino syndrome, who exhibited retinal dystrophy, acute-onset renal failure, and skeletal anomalies including bilateral coxa vara, broad femoral necks with mild bowing of the femoral diaphyses, and brachydactyly with shortened metacarpals and cone-shaped phalangeal epiphyses, Helm et al. (2017) identified homozygosity for the c.634G-A transition (c.634G-A, NM_014714.3) at the exon 6 donor splice site of the IFT140 gene, resulting in the G212R substitution at a conserved residue within the WD40 domain. His unaffected mother was heterozygous for the variant, but his father did not carry the mutation. Analysis of exome data indicated that the proband had chromosome 16 maternal heteroisodisomy, with segmental isodisomy at 16p13, suggesting that an early error in meiosis occurred in the maternal gamete. Helm et al. (2017) identified 2 different-sized PCR products from patient cells, the smaller of which was missing exon 6, resulting in frameshift and premature termination at residue 171. Functional analysis in ift140-morphant zebrafish demonstrated some improvement of gastrulation defects with the G212R mutant, but rescue was not as significant as that with wildtype IFT140, suggesting that G212R represents a partial loss-of-function variant. (less)