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11 May 2026	Intellectual disability v10.8	HS6ST2	Ida Ertmanska changed review comment from: PMID: 30471091 Paganini et al., 2019 Two Italian male twins with intellectual disability and severe myopia and an X-linked hemizygous HS6ST2 variant c.916G>C, p.Gly306Arg (maternally inherited). Psychomotor delay diagnosed at 5 years. In-vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity. PMID: 36993824 Sarmadian et al., 2023 Report of a 21mo boy from Iran, referred due to the absence of neck holding and hand tremors (manifestation of seizures). He had delayed developmental milestones such as neck holding, intellectual and walking impairment. Brain MRI showed cerebral atrophy and diffused white matter, and irregularities were seen in his EEG. He also had a ventricular septal defect. WES identified a hemizygous c.979C>T; p.Pro327Ser variant in HS6ST2 - classified as VUS, only 1 heterozygote reported in gnomAD v4.1.1. PMID: 40686562 Zhang et al., 2025 Report of a 9 month old male Chinese proband with global developmental delay. WES detected a hemizygous c.764C>A (p.Pro255Glu) variant in HS6ST2. No abnormal vision. Brain CT scan revealed a wider left lateral ventricle compared to the contralateral ventricle.; to: PMID: 30471091 Paganini et al., 2019 Two Italian male twins with intellectual disability and severe myopia and an X-linked hemizygous HS6ST2 variant c.916G>C, p.Gly306Arg (maternally inherited). Psychomotor delay diagnosed at 5 years. In-vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity. PMID: 36993824 Sarmadian et al., 2023 Report of a 21mo boy from Iran, referred due to the absence of neck holding and hand tremors (manifestation of seizures). He had delayed developmental milestones such as neck holding, intellectual and walking impairment. Brain MRI showed cerebral atrophy and diffused white matter, and irregularities were seen in his EEG. He also had a ventricular septal defect. WES identified a hemizygous c.979C>T; p.Pro327Ser variant in HS6ST2 - classified as VUS, only 1 heterozygote reported in gnomAD v4.1.1. PMID: 40686562 Zhang et al., 2025 Report of a 9 month old male Chinese proband with global developmental delay. WES detected a hemizygous c.764C>A (p.Pro255Glu) variant in HS6ST2. No abnormal vision. Brain CT scan revealed a wider left lateral ventricle compared to the contralateral ventricle. Functional evidence: PMID: 38015989 Moon et al., 2024 - Knockout of Hs6st2 in mice decreases heparan sulfate 6-O-sulfation, impairs dendritic spines of hippocampal neurons, and affects memory, providing a link to human HS6ST2-related brain disorders.
25 Jul 2019	Intellectual disability v2.978	RALA	Catherine Snow Source Expert Review Green was added to RALA. Source Expert Review was added to RALA. Added phenotypes Global developmental delay, Intellectual disability, Seizures, Abnormality of nervous system morphology for gene: RALA Publications for gene RALA were changed from to 30500825 Rating Changed from No List (delete) to Green List (high evidence)
01 Dec 2018	Intellectual disability v2.562	RALA	Konstantinos Varvagiannis gene: RALA was added gene: RALA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RALA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: RALA were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology Penetrance for gene: RALA were set to unknown Mode of pathogenicity for gene: RALA 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: RALA was set to GREEN Added comment: Hiatt et al. (doi.org/10.1371/journal.pgen.1007671) report on 11 individuals (incl. a pair of monozygotic twins) from 10 unrelated families, most (10/11) with de novo mutations in RALA. DD/ID was a prominent feature (the authors note that ID was specifically noted in 8 but could not be excluded in 3 further individuals who appear to be very young in the table). Structural brain anomalies (9/11), seizures (6/11) and common facial features were also noted. RALA belongs to the RAS superfamily of small GTPases. 5 different de novo missense variants and 1 in-frame deletion, all within a GTP/GDP binding region of RALA (although appart in the protein primary structure) were observed. 7 occurrences of missense variants concerned Val25 and Lys128 (V25M, V25L, K128R), one Asp130 (D130G) and a further one Ser157 (S157A). The in-frame deletion concerned Ala158. Missense variants in corresponding positions of RAS proteins (HRAS/KRAS/NRAS) have been reported in RASopathies, while the authors observed some phenotypic overlap with the latter group of disorders (DD/ID, growth delay, macrocephaly, high forehead and position of ears). Functional studies demonstrated reduction in GTPase activity (for all variants) and altered RALA effector binding (for most reduction - in the case of S157A, increase). Several lines of evidence are provided to show that alteration of the GTP/GTP-binding rather than a dosage effect is considered the likely mechanism. RALA is depleted in missense mutations in its GTP/GDP binding domain. For these reasons and others (segregation studies not possible, variant observed 2x in Bravo database, phenotypic differences compared to the rest of the cohort, ROH suggesting parental consanguinity in the specific individual) the single nonsense variant (R176X) reported in the study is considered a VUS. As a result, this gene can be considered for inclusion in this panel as green. Sources: Literature