1) A 19 month old girl has a clinical and radiographic course consistent with Joubert syndrome. Molecular genetic testing shows her heterozygous for a ANKS6 gene sequence variant c.532G>A, resulting in the amino acid substitution p.Glu178Lys. Prediction programs suggest this is benign, however functional and genetic evidence is deemed inconclusive. She is also heterozygous in the TMEM67 gene for an intronic variant c.1289-7A>G. The c.1289-7A>G variant may activate a cryptic AG acceptor site and interfere with normal splicing. If this new acceptor site is used, it is predicted to result in an in-frame insertion of two amino acids. In neither case was a second pathogenic mutation identified.
2) An almost 19 year old male has a progressive spastic paraparesis. Genetic testing identified a p.Ala510Val mutation in the SPG7 paraplegia gene. No second pathogenic mutation identified. SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V. It describes 4 patients who had a similar kind of mutation and developed symptoms at age 47, 1 year, 44, and 50 years of age. These patients were carrier of only 1 mutation. The SPG7 A510V was found in 8 patients (one was homozygous and 3 were controls). The paper states that these findings suggested some SPG7 mutations could be associated with variable penetrance.
The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry ( J. Neurol 2013, 260: 1286-1294). Based on review of this paper, the paper states that the change in the SPG7 was first described as a polymorphism in 1988. This was based on the frequency of 3 to 4% in 2 separate controls in the United Kingdom.
3) An 18 year old male with epilepsy has a MRI showing a linear band of T2-FLAIR hyperintense signal radiating from the subcortical white matter of the left posterior-superior temporal gyrus down towards the atrium of the left lateral ventricle. In addition, perhaps three subependymal modules were identified. There was also a tiny, linear focus of T2-FLAIR hyperintense signal extending from the right midfrontal cortex down towards the right lateral ventricle. These findings were deemed relatively mild intracranial stigmata of tuberous sclerosis.
Genetic testing revealed a sequence variant in the TSC1 gene at nucleotide position 2196 (T>C). This was deemed to be a variant of unknown significance. This variant was not predicted to change the amino acid sequence of the protein unless splicing might be affected. This was not a variant that had been identified in other index cases at Athena Diagnostics. Five splicing algorithms were used to analyze thepossible effect of this variant on splicing. None of the five algorithms predicted the elimination of a known splice site. Accordingly, data was generated to suggest that this variant may be more likely benign than pathogenic.