Cholestasis

Gene: CC2D2A

Red List (low evidence)

Both genes (TMEM67 and RPGRIP1L) are associated with a range of severe, syndromic conditions, often presenting in utero, mainly affecting kidney, or other organs than liver, including Joubert type 6, Meckel type 3, Bardet Biedl syndrome, NPHP11, RHYNS and COACH syndrome. Both genes are covered elsewhere in the following panels that match the clinical presentations: Severe paediatric disorders R14, R27, Fetal anomalies R21, Intellectual disability R29, Retinal disorders R32, Structural eye disease R36, Bardet Biedl Syndrome R107, Cystic renal disease R193, Tubulointerstitial kidney disease R202, Unexplained paediatric onset ESRD R257. Neither gene-associated classical phenotype would have cholestasis as a presenting feature, and would very likely be referred to one or more of the above alternate panels. In COACH syndrome, the presentation is syndromic, the liver involvement includes congenital hepatic fibrosis (CHF). Therefore potentially they would fit better on polycystic liver disease panel as Caroli disease (PKHD1) is commonly associated with CHF; however the testing criteria for PCLD recommends R27 (as above) or R89 Ultra-rare and atypical monogenic disorders for any complex or syndromic presentations. There is just 1 reported case with isolated CHF with 2 TMEM67 variants in the literature (PMID: 28680603) although this is very weak as 1 variant is a VUS with no supporting functional data that could be erroneous. There are no reported cases with RPGRIP1L or CC2D2A and isolated CHF. The 3rd gene associated with COACH syndrome CC2D2A was green on the 100K neonatal cholestasis panel. However looking at the evidence for the CC2D2A gene it has 2 reviews on PanelApp and was scored as red by the Bham diagnostic service and scored green by a Genomics England curator. Therefore the evidence for inclusion of these 3 COACH genes in cholestasis is limited. COACH syndrome is extremely rare with an Orphanet estimated incidence of 1 in 1,000,000. There are 34 mutations on HGMD for TMEM67 associated with COACH syndrome and just 1 mutation for RPGRIP1L. I would like to request that these 3 genes are removed from the cholestasis panel on the next update.

Created: 18 May 2020, 10:44 a.m. | Last Modified: 18 May 2020, 10:44 a.m.

Panel Version: 1.4

Publications

• 28680603

I don't know

Comment on list classification: This gene has been downgraded from Green to Grey based on expert review from Miranda Durkie (Genetics).

Created: 18 Aug 2020, 1:12 p.m. | Last Modified: 18 Aug 2020, 1:12 p.m.

Panel Version: 1.19

Comment on list classification: As discussed in the GMS Gastrohepatology Specialist Test Group webex call 14th Jan 2019: The Specialist Test Group agreed that there is enough evidence to rate this gene green. Promoted from amber to green.

Created: 28 Jan 2019, 1:49 p.m.

Initial gene list and info collated by Miranda Durkie Sheffield Diagnostic Genetics Service December 2018 on behalf of the GMS Gastrohepatology specialist test group. Gene Symbol submitted: CC2D2A; Suggested intial gene rating: Amber; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given

Created: 7 Jan 2019, 4:42 p.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Congenital hepatic fibrosis

Publications

• PMID: 19574260

Comment when marking as ready: Associated with relevant phenotypes in OMIM and as confirmed Gen2Phen gene for each phenotype. Numerous variants reported in unrelated cases.

Created: 14 Aug 2018, 8:20 a.m.

Comment on phenotypes: All three phenotypes display liver features

Created: 14 Aug 2018, 8:16 a.m.

Comment on phenotypes: Variants also reported in Joubert syndrome 9 612285, but this phenotype is not relevant to the infantile cholestasis panel

Created: 14 Aug 2018, 8:03 a.m.

Red List (low evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Ciliopathy