Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: ACD

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)

Immunodeficiency may be part of the syndromic picture of dyskeratosis congenita, especially where associated with bone marrow failure

Created: 18 Jun 2018, 3:49 p.m.

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Dyskeratosis congenita; Hoyeraal-Hreidarsson syndrome

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

Comment on phenotypes: Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, recurrent infections. Severe phenotype with developmental delay and cerebellar hypoplasia;Combined immunodeficiencies with associated or syndromic features

Created: 5 Jul 2018, 2:39 p.m.

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): TPP1 .PanelApp HGNC gene symbol check: ACD . IUIS Disease: AD/AR -DKC due to TPP1 deficiency . IUIS Inheritance: AD or AR .T cells: N/A, .B cells: Variable, .IUIS Other affected cells: N/A. IUIS Associated features: Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients. IUIS Major category: Combined immunodeficiencies with associated or syndromic features. IUIS Subcategory: DyskeratosIs Congenita (DKC), Myelodysplasia, Short Telomeres

Created: 5 Jul 2018, 2:32 p.m.

Comment on list classification: Changed Amber to Green from external clinical review comment

Created: 20 Jun 2018, 2:31 p.m.

Only two cases reported since 2015 but in view of external clinical review this gene was made green

Created: 20 Jun 2018, 2:29 p.m.

Comment on mode of inheritance: changed MOI from external review suggestion

Created: 20 Jun 2018, 2:27 p.m.

Comment on phenotypes: added phenotype suggested by expert reviewer

Created: 20 Jun 2018, 2:27 p.m.

Genetic variants of the gene ACD results in a Antibody Deficiencies type pf PID, where severely reduced serum immunoglobulins (Igs) with profoundly decreased or absent B cells (agammaglobulinemia) is observed. This type of PID is caused by: myelodysplasia with hypogammaglobuline mia (monosomy 7, trisomy 8, or dyskeratosis congenita), and thymoma with immunodeficiency with unknown genetic defect.

Created: 30 Apr 2018, 1:33 p.m.

Kept as amber until further evidence, no additional families in the literature since 2015. Added watch-list tag.

Created: 30 Apr 2018, 1:18 p.m.

Comment on publications: Added publications to support Dyskeratosis Congenita, which is a rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. There is currently (since 2015) only two families been described, one one family with autosomal dominant inheritance had only progressive bone marrow failure and one patient (patient B) with autosomal recessive inheritance had a more severe phenotype.

Created: 30 Apr 2018, 1:18 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 supplied by GRID. GRID Gene Symbol HGNC PanelApp check: ACD, GRID_Gene_Symbol: ACD, GRID_Transcript_ENS_Community submitted: ENST00000219251, GRID_Transcript_RefSeq: NM_001082486.1, GRID_Transcript_ENS_used_on_Production: ENST00000219251

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