| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Intellectual disability v4.26 | PAFAH1B1 | Arina Puzriakova Phenotypes for gene: PAFAH1B1 were changed from PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia; LISSENCEPHALY TYPE 1 (LIS1) to Lissencephaly 1, OMIM:607432; Subcortical laminar heterotopia, OMIM:607432 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v4.25 | DCX | Arina Puzriakova Phenotypes for gene: DCX were changed from Lissencephaly, X-linked, 300067Subcortical laminal heteropia, X-linked, 300067; SUBCORTICAL BAND HETEROTOPIA X-LINKED (SBHX) to Lissencephaly, X-linked, OMIM:300067; Subcortical laminal heterotopia, X-linked, OMIM:300067 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.1558 | SLC35B2 |
Konstantinos Varvagiannis gene: SLC35B2 was added gene: SLC35B2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC35B2 were set to 35325049 Phenotypes for gene: SLC35B2 were set to Abnormality of the skeletal system; Short long bone; Short stature; Abnormality of epiphysis morphology; Scoliosis; Multiple joint dislocation; Global develpmental delay; Intellectual disability; CNS hypomyelination; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of the amniotic fluid Penetrance for gene: SLC35B2 were set to Complete Review for gene: SLC35B2 was set to AMBER Added comment: 2 unrelated individuals with biallelic SLC35B2 variants have been reported. DD and ID were part of the phenotype. There is currently no associated phenotype in OMIM/G2P/SysID. The gene has amber rating in the leukodystrophies panel of PanelApp Australia. Consider inclusion in the current panel (or other possibly relevant ones eg. for skeletal disorders, short stature, white matter disorders, corpus callosum, etc) with amber rating. --- Guasto et al (2022 - PMID:35325049) report 2 unrelated individuals with biallelic SLC35B2 variants. SLC35B2 encodes solute carrier family 35 (3'-phosphoadenosine 5'-phosphosulfate (PAPS) transporter), member B2. The protein is located in the Golgi membrane and serves as transporter of the activated nucleotide sulfate PAPS from the cytosol, where it is synthesized to the Golgi lumen. Another PAPS transporter is encoded by SLC35B3. In the Golgi apparatus PAPS serves as substrate of sulfotransferases for the addition sulfate to the covalently attached GAG chains of proteoglycans (PGs). The phenotype corresponded to a chondrodysplasia manifesting as severe pre- and postnatal growth retardation (height <-4 SD and -8 SD), early scoliosis, multiple joint dislocations (in one). There was severe DD affecting motor and expressive language development with associated ID. Brain imaging was suggestive of hypomyelinating leukodystrophy with thin corpus callosum and cerebral atrophy. One individual had a cleft palate in the context of Pierre Robin sequence. Both individuals were investigated with exome sequencing. The first individual - born to consanguineous parents - was homozygous for an in-frame del (NM_178148.3:c.1218_1220del, p.Leu407del) with Sanger sequencing confirming the variants, and heterozygosity in parents and 2 unaffected sibs. There was an initially identified hmz CUL7 variant (for 3M syndrome), which was not felt sufficient to explain the severity of the phenotype and notably ID. The 2nd proband was homozygous for a fs variant (c.1224_1225delAG / p.Arg408SerfsTer18 - leading to loss of the last 8 amino acids) occurring in the context of uniparental isodisomy [iUPD(6)] spanning the complete chr6 based on the exome data. Among the evidence presented for SLC35B2 and the variants : - SLC35B2 has high mRNA expression in fetal and adult mouse brain and other tissues. - Upon qPCR analysis of mRNA expression in human brain samples, the gene had expression across the brain (frontal lobe grey matter, subcortical frontal white matter/cerebellum). - High expression was shown upon analysis of mouse brain single cell RNA data (EMBL) in oligodendrocytes and microglial cells. - RT-PCR on mRNA from skin fibroblasts (both individuals) revealed significant decrease of SCL35B2 mRNA levels compared to controls. - Transfection of C-terminal c-myc tagged wt or mutant proteins in HEK293F cells, followed by western blotting did not reveal significant difference at the protein level. Wt SLC35B2 localized at the Golgi apparatus as suggested by colocalization with GM130 marker. The 2 variants however displayed only partial colocalization (/loss of localization specificity) with diffuse signal in the cell. - Chondroitin sulfate disaccharide sulfation was decreased upon HPLC disaccharide analysis in patient fibroblasts and bikunin (a circulating proteoglycan in blood) electrophoretic pattern in patient sera. - Disorders due to variants in genes implicated in proteoglycan biogenesis (e.g. XYLT1, B3GALT6, CHSY1) are associated with skeletal/connective tissue manifestations with DD/ID. - C-elegans model lacking pst-1 (SLC35B2 ortholog) provides support that the protein is required for migration, axonal guidance, and presynaptic development in a subset of neurons. - dsm-1 - the rat ortholog - is expressed in rat brain in D-serine and NMDA receptor rich regions. When expressed in Xenopus oocytes it accelerated the efflux of D-serine (a co-agonist for NMDA receptor). - Variants in other members of SLC superfamily (e.g. SLC17A5, SLC35A3, SLC29A3, SLC35A2) have been associated with brain-bone phenotypes. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.1542 | HEPACAM | Arina Puzriakova Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD), 613926; Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR), 613925 to Megalencephalic leukoencephalopathy with subcortical cysts 2A, OMIM:613925; Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation, OMIM:613926 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.432 | BCORL1 | Arina Puzriakova Phenotypes for gene: BCORL1 were changed from Intellectual disability, developmental delay and dysmorphism; Behavioral abnormality to Shukla-Vernon syndrome, 301029 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.431 | BCORL1 | Arina Puzriakova Publications for gene: BCORL1 were set to 24123876; 24896178; 26350204; 30941876 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.430 | BCORL1 | Arina Puzriakova Classified gene: BCORL1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.430 | BCORL1 | Arina Puzriakova Gene: bcorl1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.3 | TUBGCP2 |
Zornitza Stark gene: TUBGCP2 was added gene: TUBGCP2 was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TUBGCP2 were set to 31630790 Phenotypes for gene: TUBGCP2 were set to Lissencephaly; pachygyria; subcortical band heterotopia; microcephaly; intellectual disability Review for gene: TUBGCP2 was set to GREEN gene: TUBGCP2 was marked as current diagnostic Added comment: Four unrelated families reported. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.0 | BCORL1 | Zornitza Stark reviewed gene: BCORL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24123876, 30941876; Phenotypes: Shukla-Vernon syndrome, MIM# 301029; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.857 | BCORL1 | Rebecca Foulger Tag watchlist tag was added to gene: BCORL1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.857 | BCORL1 | Rebecca Foulger Classified gene: BCORL1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.857 | BCORL1 | Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on external review by Konstantinos Varvagiannis and the new paper Shukla et al., 2019 (PMID:30941876). The original Asn820Ser variant from Schuurs-Hoeijmakers et al., 2013 (PMID:24123876) is still listed as a VUS in OMIM due to a lack of evidence for association with the ID phenotype. Although Shukla et al report 3 cases with 3 new BCORL1 variants (two unrelated males and a further three brothers), patient 2 does not have ID, but instead has typical early motor milestones, and speech delay. ID is also mild in Patient 1. Based on 2 clear cases plus 1 potential case from Shukla et al,. I have rated Amber and added a 'watchlist' tag awaiting further reports. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.857 | BCORL1 | Rebecca Foulger Gene: bcorl1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.856 | BCORL1 | Rebecca Foulger Publications for gene: BCORL1 were set to 24123876; 24896178; 26350204 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.855 | BCORL1 | Rebecca Foulger Phenotypes for gene: BCORL1 were changed from to Intellectual disability, developmental delay and dysmorphism; Behavioral abnormality | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.854 | BCORL1 | Rebecca Foulger Mode of inheritance for gene: BCORL1 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.800 | BCORL1 | Konstantinos Varvagiannis reviewed gene: BCORL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24123876, 30941876; Phenotypes: Global developmental delay, Intellectual disability, Autism, Behavioral abnormality; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.735 | HEPACAM | Ivone Leong Phenotypes for gene: HEPACAM were changed from Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD); Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR) to Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without mental retardation (AD), 613926; Megalencephalic leukoencephalopathy with subcortical cysts 2A (AR), 613925 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v2.468 | BCOR | Louise Daugherty Source Victorian Clinical Genetics Services was added to BCOR. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | BCOR | BRIDGE consortium edited their review of BCOR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | BCOR | BRIDGE consortium edited their review of BCOR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | BCOR | BRIDGE consortium reviewed BCOR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||