Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CHD7

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

Green List (high evidence)

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): CHD7 .PanelApp HGNC gene symbol check: CHD7 . IUIS Disease: CHARGE syndrome due to CHD7 deficiency . IUIS Inheritance: AD .T cells: Very low, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Coloboma, heart anomaly, choanal atresia, intellectual disability, genital and ear anomalies, CNS malformation, some are SCID-like and have low TRECs. IUIS Major category: Combined immunodeficiencies with associated or syndromic features. IUIS Subcategory: Thymic Defects with Additional Congenital Anomalies

Created: 2 Jul 2018, 10:35 a.m.

Comment on list classification: Changed from Amber to Green. Although the support for specific PID phenotypes is not conclusive, there is enough evidence to support immune dysfunction association in general caused by CHD7 in CHARGE syndrome, especially in common in early infancy.

Created: 7 Jun 2018, 10:58 a.m.

Comment on phenotypes: added MIMid from OMIM

Created: 7 Jun 2018, 10:48 a.m.

Comment on publications: added papers to support PID phenotype. Immunological dysfunction, which predominantly affects T-cell function, has occasionally been described in patients with CHARGE syndrome. Mutations CHD7 gene have been identified in up to 90% of patients with CHARGE syndrome, Bergman et al., 2011 (PMID:21378379 ) and Janssen et al., 2012. (PMID:22461308).Immunodeficiency in individuals with CHARGE syndrome is not unexpected given the potential for thymic maldevelopment; however, its prevalence and severity remain poorly defined because of a general lack of published systemic assessment from large CHARGE cohorts. Most reports are of single case descriptions or retrospective series, invariably resulting in a publication bias of more severe phenotypes. However the severity of immunodeficiency in CHARGE syndrome can vary from asymptomatic derangements in absolute T‐cells to life threatening severe combined immunodeficiency (SCID), also termed complete Di George anomaly.

Created: 7 Jun 2018, 10:18 a.m.

Comment on phenotypes: CHARGE syndrome is caused by a dominant variant in the CHD7 gene. Multiple organ systems can be affected because of haploinsufficiency of CHD7 during embryonic development. Immunodeficiency in CHARGE syndrome review PMID: 29159871 (2017) indicates that CHARGE syndrome can present with the immunological phenotypes and can include : Presentions with infections, Lymphopenia, Reduced CD3 T-cells, Reduced CD8 T‐cell, Thymic hypoplasia or aplasia, Humoral defect (in some).

Created: 7 Jun 2018, 10:10 a.m.

Comment on mode of inheritance: Noted on IUIS that mode of inheritance is De novo defect (majority) or AD

Created: 6 Jun 2018, 2:25 p.m.

From Mehr et al. (2017) PMID: 29159871. CHARGE is an acronym that classically describes a syndrome which iscomprised of Coloboma, Heart defects, Atresia of the choanae,Retardation of growth and/or development, Genitourinary abnormali-ties, and Ear anomalies. The disorder is more complex than the acronym suggests, with other systemspotentially involved including the immune system. Immunodeficiency in CHARGE syndrome is rare, and occurslargely due to impairment in thymic development, and thus functional T-cell production. The severity of the immunodeficiency relates tothe degree of thymic maldevelopment. Complete thymic aplasia,although very rare, results in a severe immunodeficiency withcomplete/near complete absence of T-cells and abnormal B-cellfunction with associated hypogammaglobulinaemia. Without effec-tive immune reconstitution these children will die from infection.Partial thymic aplasia may result in no detectable defect at all, mildreduction in T-cells with no clinical consequence, or more significantreduction in T-cells with associated B-cell function impairment,resulting in recurrent infections which will require prophylacticantibiotics and/or immunoglobulin infusions but not immunereconstitution. Pure B-cell or antibody defects are rarely described in CHARGE syndrome

Created: 6 Jun 2018, 2:19 p.m.

Comment on publications: added publications to support CHARGE syndrome wth immunological phenotype

Created: 6 Jun 2018, 2:17 p.m.

Comment on publications: added review paper (2017) PMID: 29159871 Immunodeficiency in CHARGE syndrome.

Created: 6 Jun 2018, 2:10 p.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 20 Apr 2018, 12:25 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: CHARGE-CHD7, PanelApp HGNC gene symbol check: CHD7, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Other well defined PIDs / CHARGE syndrome / CHARGE syndrome

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: CHD7, GRID_Gene_Symbol: CHD7, GRID_Transcript_ENS_Community submitted: ENST00000423902, GRID_Transcript_RefSeq: NM_017780.2, GRID_Transcript_ENS_used_on_Production: ENST00000423902

Created: 17 Apr 2018, 12:12 p.m.