Intellectual disability - microarray and sequencing
Gene: FGFR1
Gene was reassessed in view of Zornitza's review highlighting that Hartsfield syndrome, caused by germline FGFR1 variants, is associated with significant ID. Although severe cognitive impairment is a feature, cases present in a syndromic manner and there is no precedent for presentation with ID alone. We would expect this phenotype to be picked up via the other GMS panels (e.g. Holoprosencephaly, Skeletal dysplasia, Fetal anomalies, Cleft palate, etc) for which this gene is already Green.
Given the large number of disorders associated with this gene, the gain from inclusion on the ID panel is probably smaller than the risk of incidental information for the majority of the ID cohort. Therefore maintaining Red gene rating in line with previous reviews.Created: 25 Jan 2021, 12:54 p.m. | Last Modified: 25 Jan 2021, 12:54 p.m.
Panel Version: 3.731
In view of recent external expert Green review this gene was reaccessed by curation and internal clinical team. It was decided to keep this gene Red on our Intellectual disability (ID) panel. The reason for not promoting this gene to Green: Encephalocraniocutaneous lipomatosis (ECCL) has been identified on testing affected tissue in view of the somatic mosaic nature. The pick up from germline analysis is untested, our current pipeline is not optimised for mosaicism, so it is unlikely to high. In view of the large range of disorders associated with this gene, and ID not being a feature of the majority, there would seem to be a greater chance of extraneous findings wrt this panel than diagnostic findings if it were rated green.Created: 12 Sep 2018, 2:52 p.m.
Gene causes several phenotypes but this specific phenotype caused by germline variants is associated with significant ID.Created: 3 Feb 2020, 2:13 a.m. | Last Modified: 3 Feb 2020, 2:13 a.m.
Panel Version: 3.0
Please note that somatic mutations in this gene cause ECCL, MIM#613001, which is associated with intellectual disability PMID 26942290Created: 17 Jun 2018, 7:49 p.m.
Mode of inheritance
Other
Phenotypes
Hartsfield syndrome, MIM# 615465
Publications
Variants in this GENE are reported as part of current diagnostic practice
Comment when marking as ready: Causation is clear for Pfeiffer syndrome, Kallman and Osteoglophonic dysplasia. Although ID is a reported feature of Pfeiffer syndrome, it is not universal and the condition would be expected to present in a syndromic manner with craniosynostosis prior to ID. This, along with the fact that it is caused by a recurrent missense variant, means that the utility of calling all variants in this gene in a cohort that includes non-syndromic ID is unlikely to be of benefit.Created: 21 Dec 2017, 10:20 a.m.
Comment on list classification: Causation is clear for Pfeiffer syndrome, Kallman and Osteoglophonic dysplasia. Although ID is a reported feature of Pfeiffer syndrome, it is not universal and the condition would be expected to present in a syndromic manner with craniosynostosis prior to ID. This, along with the fact that it is caused by a recurrent missense variant, means that the utility of calling all variants in this gene in a cohort that includes non-syndromic ID is unlikely to be of benefit.Created: 21 Dec 2017, 10:20 a.m.
This is a confirmed DD gene for Kallmann syndrome type 2 and Pfeiffer syndrome, which include the HPO term intellectual disability. It is a confirmed DD gene for Osteoglophonic dysplasia, which has delayed speech and language development as a phenotype.Created: 13 Dec 2017, 9:46 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
KALLMANN SYNDROME TYPE 2; Pfeiffer syndrome 101600
Publications
Phenotypes
OSTEOGLOPHONIC DYSPLASIA (OGD)
This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_UKGTN_v12 . Main mutation mechanism : Activating; Loss of functionCreated: 27 Jul 2017, 5:49 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; ddg2p_201507; ddg2p_201507_conf; UKGTN_v12; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_red_20160217; neuro_20160418_strict; Activating; Loss of function. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation TrustCreated: 19 Jul 2017, 12:27 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Mode of pathogenicity
Other
Phenotypes for gene: FGFR1 were changed from Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600 to Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600; Encephalocraniocutaneous lipomatosis, somatic mosaic, OMIM:613001
Publications for gene: FGFR1 were set to 28825856
Phenotypes for gene: FGFR1 were changed from Encephalocraniocutaneous lipomatosis, 613001; KALLMANN SYNDROME TYPE 2; Pfeiffer syndrome,101600 to Hartsfield syndrome, OMIM:615465; Pfeiffer syndrome, OMIM:101600
Source Victorian Clinical Genetics Services was added to FGFR1.
Phenotypes for gene: FGFR1 were set to Encephalocraniocutaneous lipomatosis, 613001; KALLMANN SYNDROME TYPE 2; Pfeiffer syndrome,101600
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Model of inheritance for gene FGFR1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene FGFR1 was set to ['28825856']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
FGFR1 was added to Intellectual disabilitypanel. Source: Expert Review Red
FGFR1 was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen