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| Skeletal ciliopathies v0.19 | KIAA0753 |
Eleanor Williams changed review comment from: Provisionally associated with ?Orofaciodigital syndrome XV (617127) in OMIM PMID: 26643951 - Chevrier et al 2016 - 1 case of a newborn female presenting with an oral-facial-digital (OFD) VI syndrome in which they identified two causal heterozygous mutations in the KIAA0753 gene. Both KIAA0753 mutations, one nonsense variant (c.1891A>T; p.Lys631*) and one substitution in Intron 8 (c.1546-3C>A), were confirmed by Sanger sequencing, as well as the maternal heterozygous status for the non-sense variant. The sporadic occurrence of the c.1546-3C>A variant was confirmed by samples concordance. cDNA analysis indicates the intronic variant results in skipping of Exon 8 that caused a frameshift, changed the amino acids sequence and led to the occurrence of a premature stop codon. Because both mutations appeared truncating and probably compound heterozygous, they were considered as potentially causal. PMID: 28220259 - Stephen et al 2017 - 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). Brain MRI of the younger sibling revealed the “molar tooth sign”, and she had global developmental delay. The older sibling was diagnosed after the younger sibling, and brain MRI showed an ectopic posterior pituitary gland in addition to the molar tooth sign. Hypotonia and global developmental delay were noted at 10 months. The parents were each heterozygous for one of the variants. Cilia formation in primary fibroblasts from patients was signficantly lower than in controls. PMID: 29138412 - Hammarsjö et al 2017 - report biallelic pathogenic variants in KIAA0753 in four patients from 3 families with short-rib type skeletal dysplasia - ranging from prenatal lethality in one fetus to viability with moderate skeletal dysplasia in three children. 2 families had the same homozygous nonsense variant but are not thought to be related. In the 3rd family the index patient was compound heterogyzous. KIAA0753 is expressed in normal fetal human growth plate and they show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning. In family 1, they also identified an additional homozygous missense variant, c.425 C > T (p.Thr142Met) in SLC13A5 and conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant. ; to: Provisionally associated with ?Orofaciodigital syndrome XV (617127) in OMIM PMID: 26643951 - Chevrier et al 2016 - 1 case of a newborn female presenting with an oral-facial-digital (OFD) VI syndrome in which they identified two causal heterozygous mutations in the KIAA0753 gene. Both KIAA0753 mutations, one nonsense variant (c.1891A>T; p.Lys631*) and one substitution in Intron 8 (c.1546-3C>A), were confirmed by Sanger sequencing, as well as the maternal heterozygous status for the non-sense variant. The sporadic occurrence of the c.1546-3C>A variant was confirmed by samples concordance. cDNA analysis indicates the intronic variant results in skipping of Exon 8 that caused a frameshift, changed the amino acids sequence and led to the occurrence of a premature stop codon. Because both mutations appeared truncating and probably compound heterozygous, they were considered as potentially causal. PMID: 28220259 - Stephen et al 2017 - 2 siblings with Joubert syndrome associated with growth hormone deficiency but no oral or digital anomalies. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). Brain MRI of the younger sibling revealed the “molar tooth sign”, and she had global developmental delay. The older sibling was diagnosed after the younger sibling, and brain MRI showed an ectopic posterior pituitary gland in addition to the molar tooth sign. Hypotonia and global developmental delay were noted at 10 months. The parents were each heterozygous for one of the variants. Cilia formation in primary fibroblasts from patients was signficantly lower than in controls. PMID: 29138412 - Hammarsjö et al 2017 - report biallelic pathogenic variants in KIAA0753 in four patients from 3 families with short-rib type skeletal dysplasia - ranging from prenatal lethality in one fetus to viability with moderate skeletal dysplasia in three children. 2 families had the same homozygous nonsense variant but are not thought to be related. In the 3rd family the index patient was compound heterogyzous. KIAA0753 is expressed in normal fetal human growth plate and they show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning. In family 1, they also identified an additional homozygous missense variant, c.425 C > T (p.Thr142Met) in SLC13A5 and conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant. |
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| Skeletal ciliopathies v0.1 | KIAA0753 |
Eleanor Williams gene: KIAA0753 was added gene: KIAA0753 was added to Skeletal ciliopathies. Sources: Literature,Expert Review Green Mode of inheritance for gene: KIAA0753 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA0753 were set to 29138412; 28220259; 26643951 Phenotypes for gene: KIAA0753 were set to ?Orofaciodigital syndrome XV 617127; Joubert syndrome; Short-rib skeletal dysplasia |
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