Activity

Filter

Cancel
Date Panel Item Activity
31 actions
Early onset or syndromic epilepsy v2.271 FLNA Sarah Leigh Phenotypes for gene: FLNA were changed from Heterotopia, periventricular 300049 to Heterotopia, periventricular OMIM:300049
Early onset or syndromic epilepsy v2.0 DLL1 Konstantinos Varvagiannis gene: DLL1 was added
gene: DLL1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: DLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLL1 were set to 31353024
Phenotypes for gene: DLL1 were set to Global developmental delay; Intellectual disability; Morphological abnormality of the central nervous system; Seizures; Behavioral abnormality; Autism; Scoliosis
Penetrance for gene: DLL1 were set to unknown
Review for gene: DLL1 was set to AMBER
Added comment: Gene added to the ID panel. Epilepsy has been reported in 6 unrelated individuals. Please consider inclusion with amber/green rating.

----

Heterozygous DLL1 pathogenic variants cause Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (# 618709).

Fischer-Zirnsak et al (2019 - PMID: 31353024) reported on 15 affected individuals from 12 unrelated families.

Most common features included DD/ID (12/14), ASD (6/14 - belonging to 6 families) or other behavioral abnormalities, seizures (6/14 - from 6 unrelated families) and various brain MRI abnromalities. As commented by OMIM (based on the same ref) "Cognitive function ranges from severely impaired to the ability to attend schools with special assistance". Among other features, scoliosis was observed in 4. The authors could not identify a distinctive facial gestalt.

Variable initial investigations (where discussed/performed - also suggesting relevance to the current panel) included CMA, FMR1, FLNA, mitochondrial DNA analysis and metabolic work-up but had not revealed an alternative cause.

The DLL1 variants were identified by WES (with the exception of a 122-kb microdeletion spanning DLL1 and FAM120B detected by CMA). Nonsense, frame-shift, splice-site variants in positions predicted to result to NMD were identified in most. One individual was found to harbor a missense variant (NM_005618.3:c.536G>T / p.Cys179Phe) and another the aforementioned microdeletion.

The variant in several individuals had occurred as a de novo event. In 2 families, it was inherited from an also affected parent (an unaffected sib was non-carrier) while in 3 families parental studies were not possible/complete.

In frame insertion of 4 residues was demonstrated for a splice site variant, from LCLs of the corresponding individual. For another individual, material was unavailable for mRNA studies. The missense variant affected a cysteine (of the DSL domain) conserved in all Notch ligands while AA changes affecting the same position of JAG1 (another Notch ligand) have been described in patients with Alagille s.

Based on the variants identified and reports of deletions spanning DLL1 in the literature, haploinsufficiency is the proposed underlying mechanism. The gene has also a pLI of 1 and %HI of 4.65.

DLL1 encodes the Delta-like canonical Notch ligand 1. Notch signaling is an established pathway for brain morphogenesis. Previous in vivo and in vitro studies have demonstrated the role of DLL1 in CNS. The gene is highly expressed in neuronal precursor cells during embryogenesis. Expression of Dll1 (and other molecules of the Notch signalling pathway) in an oscillatory/sustained pattern and cell-cell interactions important for this pathway have been demonstrated to play a role in neuronal differentiation. [Most discussed by Fischer-Zirnsak et al with several refs provided / also Gray et al., 1999 - PMID: 10079256 & OMIM].

Animal models as summarized by the authors:
[Mouse] Loss of Dll1 in mice has been shown to increase neuronal differentiation, cause CNS hyperplasia and increased number of neurons (PMIDs cited: 9109488, 12397111, 20081190). Reduced Dll1 expression was associated with scoliosis and mild vertebral defects (cited PMIDs: 19562077, 14960495, 22484060 / among others Dll1 haploinsufficiency and dominant negative models studied). Scoliosis and vertebral segmentation defects were features in 4 and 1 individual, respectively in the cohort of 15.
[Zebrafish] Homozygous mutations in dlA, the zebrafish ortholog, disrupted the Delta-Notch signaling and led to patterning defects in the hindbrain and overproduction of neurons (cited: 15366005).
Sources: Literature
Early onset or syndromic epilepsy v1.474 FLNA Rebecca Foulger changed review comment from: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was notes that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.; to: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was noted that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.
Early onset or syndromic epilepsy v1.434 FLNA Rebecca Foulger Added comment: Comment on mode of inheritance: At the Webex call 22nd November 2019, it was notes that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.
Early onset or syndromic epilepsy v1.434 FLNA Rebecca Foulger Mode of inheritance for gene: FLNA was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.433 FLNA Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating of FLNA as Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy, and following Green ratings by Alisdair McNeill and Alison Callaway: Agreed that there is enough evidence to rate this gene Green. Kept rating of FLNA as Green.
Early onset or syndromic epilepsy v1.433 FLNA Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating as Green.; to: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating of FLNA as Green.
Early onset or syndromic epilepsy v1.433 FLNA Rebecca Foulger commented on gene: FLNA: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Kept rating as Green.
Early onset or syndromic epilepsy v1.425 FLNA Alison Callaway reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.352 FLNA alisdair mcneill reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.351 FLNA Rebecca Foulger edited their review of gene: FLNA: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Early onset or syndromic epilepsy v1.263 FLNA Rebecca Foulger Source North West GLH was added to FLNA.
Early onset or syndromic epilepsy v1.262 KCNA1 Rebecca Foulger commented on gene: KCNA1: Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)
Early onset or syndromic epilepsy v1.262 SCN9A Rebecca Foulger commented on gene: SCN9A: Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)
Early onset or syndromic epilepsy v1.262 FLNA Rebecca Foulger commented on gene: FLNA: Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)
Early onset or syndromic epilepsy v1.230 FLNA Rebecca Foulger Marked gene: FLNA as ready
Early onset or syndromic epilepsy v1.230 FLNA Rebecca Foulger Gene: flna has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.230 FLNA Rebecca Foulger commented on gene: FLNA: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.
Early onset or syndromic epilepsy v1.191 FLNA Rebecca Foulger Source Wessex and West Midlands GLH was added to FLNA.
Early onset or syndromic epilepsy v1.190 FLNA Rebecca Foulger Source NHS GMS was added to FLNA.
Early onset or syndromic epilepsy v1.189 FLNA Rebecca Foulger edited their review of gene: FLNA: Added comment: Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Amber. ; Changed rating: AMBER
Early onset or syndromic epilepsy v1.188 FLNA Tracy Lester reviewed gene: FLNA: Rating: AMBER; Mode of pathogenicity: ; Publications: 20014127; Phenotypes: Heterotopia periventricular, 1 300049; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.176 FLNA Rebecca Foulger Publications for gene: FLNA were set to 15668422; 20014127; 25755106
Early onset or syndromic epilepsy v1.175 FLNA Rebecca Foulger Publications for gene: FLNA were set to
Early onset or syndromic epilepsy v1.174 FLNA Rebecca Foulger commented on gene: FLNA: PMID:25755106. In a woman and her 3 daughters with a complex phenotype comprising both periventricular nodular heterotopia and Melnick-Needles syndrome, Parrini et al. (2015) identified a c.622G-C transversion in exon 3 of the FLNA gene (G208R). The 3 daughters had onset of seizures in the first decade.
Early onset or syndromic epilepsy v1.174 FLNA Rebecca Foulger commented on gene: FLNA: PMID:20014127. In an 18-month-old girl with periventricular nodular heterotopia and seizures, Jefferies et al. (2010) identified a heterozygous 7896G-A transition in the FLNA gene (W2632X).
Early onset or syndromic epilepsy v1.174 FLNA Rebecca Foulger commented on gene: FLNA
Early onset or syndromic epilepsy FLNA Sarah Leigh marked gene: FLNA as ready
Early onset or syndromic epilepsy FLNA Sarah Leigh classified FLNA as Green List (high evidence)
Early onset or syndromic epilepsy FLNA Zornitza Stark reviewed gene: FLNA
Early onset or syndromic epilepsy FLNA Sarah Leigh Added gene to panel