RTTN was first reported in relation to autosomal recessive microcephalic primordial dwarfism in 2012 (Kheradmand Kia et al., PMID: 22939636). Affected probands present with microcephaly, brain malformations, short stature, and developmental delay, each of varying severity. Some of the earlier patients reported, such as from Shamseldin et al. (PMID: 26608784) were diagnosed with primordial dwarfism, a condition where height and weight are both more than 3 standard deviations below the mean at birth, leading to short stature lasting into adulthood. However, other reports simply describe probands as having short stature, without giving specific measurements (PMID: 26846091), and other cases are fetal/neonatal lethal, with probands presenting with intrauterine growth restriction (PMID: 30879067, 32058062). Because of this, the degree of short stature that may be associated with biallelic variants in this gene is currently unclear. Thirteen variants (missense, nonsense, frameshift, splicing) that have been reported in 17 probands in 5 publications (PMID: 22939636, 26608784, 26846091, 26940245, 30879067) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be biallelic loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, cell culture model, and interaction evidence; PMID: 11900971, 28811500). A mouse model indicates that the homozygotes are significantly smaller than the wild-type in the embryonic period, with dysmorphisms and defective axial rotation. None of the homozygotes live past the embryonic stage. Interaction evidence shows that RTTN interacts directly with STIL, which was classified as definitive for autosomal recessive primary microcephaly. Cell culture evidence shows impaired centriole duplication in the mutants. In summary, there is definitive evidence supporting the relationship between RTTN and autosomal recessive microcephalic primordial dwarfism. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date 10/22/2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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