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| Genetic Epilepsy v0.2183 | KAT6A | Elena Savva Marked gene: KAT6A as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.2183 | KAT6A | Elena Savva Gene: kat6a has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.2183 | KAT6A | Elena Savva Classified gene: KAT6A as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.2183 | KAT6A | Elena Savva Gene: kat6a has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic Epilepsy v0.2182 | KAT6A |
Elena Savva gene: KAT6A was added gene: KAT6A was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: KAT6A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KAT6A were set to PMID: 34748993 Phenotypes for gene: KAT6A were set to Arboleda-Tham syndrome MIM#616268 Review for gene: KAT6A was set to GREEN Added comment: PMID: 34748993 - 2 new probands with KAT6A syndrome and epilepsy. Proband 1 - Epilepsy onset was at 3 months of age when daily right hemiclonic seizures appeared in sleep. Had a de novo missense, previously reported as pathogenic. Proband 2 - Seizures onset was at 5 months with daily clusters of symmetric spasms characterized by flexion of the arms, extension of the legs and eyes’ rolling. Had a de novo PTC Paper then reviews literature, notes 17/90 probands had epilepsy Sources: Literature |
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| Genetic Epilepsy v0.776 | KAT5 |
Konstantinos Varvagiannis gene: KAT5 was added gene: KAT5 was added to Genetic Epilepsy. Sources: Literature Mode of inheritance for gene: KAT5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KAT5 were set to 32822602 Phenotypes for gene: KAT5 were set to Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face Penetrance for gene: KAT5 were set to unknown Mode of pathogenicity for gene: KAT5 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: KAT5 was set to GREEN Added comment: Humbert el al (2020 - PMID: 32822602) report 3 individuals with de novo missense KAT5 variants. Features included severe DD (3/3) and ID (2/2 - the 3rd was 18m on last examination), microcephaly (2/3), behavioral anomalies (3/3) including severe sleep disorder (3/3 - table S1 / night walking, sleep onset delay, excessive daytime sleepiness), seizures (3/3 - variable type and age of onset), brain MRI abnormalities (3/3 - CC, cerebellar atrophy each in 2 subjects, focal polymicrogyria in 1), various genitourinary anomalies (3/3). All had moderately short stature (-1.95 SD to -2.9SD). Cleft LP and submucous cleft P were observed in 2/3. Facial features included round face, flat profile, depressed nasal bridge, downturned corners of mouth and prognathism (each in at least 2 subjects). KAT5 encodes a lysine acetyltransferase involved in gene expression, DNA repair, chromatine remodeling, apoptosis and cell proliferation. It is part of the NuA4 histone acetyltransferase (HAT) complex also called TIP60/p400 (TIP60 being another name for KAT5). Regulation by histone acetylation is important for proper development. 3 missense KAT5 SNVs were identified, one within the chromobarrel domain (aa 7-65 / NM_006388.3) and 2 in the acetyl-CoA binding domain (aa 365-420). Following generation of K562 cells expressing either WT or variants, it was demonstrated that wt/mt KAT5 assemble normally into NuA4/TIP60 complexes. Histone acetyltransferase activity was however impaired for all variants, suggesting a partial loss of function mechanism. As Humbert et al comment, it is possible that KAT5 haploinsufficiency does not lead to a syndrome. Over 10 high-confidence LoF variants are listed in gnomAD. Heterozygous Kat5 ko mice have normal development, growth and fertility. Homozygous ko mice are embryonic lethal. In haploinsufficient mice, reduction of mRNA to 50% has been shown to be compensated at the protein level in adipose and/or other tissues (several studies cited). RNA-Seq in fibroblasts from 2 affected individuals revealed dysregulation of highly relevant genes (e.g. for neurodevelopment, circadian clock, etc). Mutations in KAT6A/B, encoding two other acetyltransferases cause neurodevelopmental disorders with features overlapping those observed in individuals with KAT5 variants (e.g. DD/ID, microcephaly, seizures, sleep disturbance, clefts, CC or genital anomalies). Consider inclusion in the ID and epilepsy panels with green rating as well as the gene panel for clefting with amber. Sources: Literature |
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