Severe microcephaly

Gene: DPP6

I don't know

DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).
The ClinGen Gene-Disease Validity score for this gene is "Disputed" (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T160000.000Z) therefore, this gene will made red.

Created: 29 Aug 2024, 2:52 p.m. | Last Modified: 29 Aug 2024, 3:46 p.m.

Panel Version: 6.4

I don't know

The rating of this gene has been updated to Amber following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 1:14 p.m. | Last Modified: 2 May 2024, 1:14 p.m.

Panel Version: 5.4

This gene is being assessed for demotion from green to amber, and has the to_be_confirmed tag added as this is still under consideration. Added the Q4_21_rating tag to make it clear that it is the rating that is being assessed.

Created: 6 Oct 2022, 2:16 p.m. | Last Modified: 6 Oct 2022, 2:16 p.m.

Panel Version: 2.319

I don't know

PMID: 23832105
- 1x proband (OFC < -3 SD) with a missense which segregated in 3 other family members
- 2x probands with 336kb deletion. Both OFCs < -3 SD
- mouse KO model with significantly smaller brain weight

However, note that missense was found using candidate gene approach in a cohort of microcephalic patients. There have been no further reports since 2013. A single LP variant is present in ClinVar but associated with schizophrenia.

Created: 2 Sep 2020, 9:28 p.m. | Last Modified: 2 Sep 2020, 9:28 p.m.

Panel Version: 2.20

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Mental retardation, autosomal dominant 33 (MIM#616311)

Publications

• 23832105

I don't know

As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is enough evidence to rate this gene Green

Created: 29 Jul 2019, 4:18 p.m. | Last Modified: 29 Jul 2019, 4:18 p.m.

Panel Version: 1.62

Comment on list classification: Updated rating from Red to Green based on 3 unrelated cases described in PMID:23832105- 2 deletions and a missense.

Created: 2 Mar 2017, 2:55 p.m.

Added 'deletions' tag based on 2 deletions (336 kb and 362 kb) described in PMID:23832105.

Created: 2 Mar 2017, 11:49 a.m.

PMID:23832105 (Liao et al., 2013) identify 2 de novo deletions and 1 missense mutation in familial microcephalic patients.
A 5 year old girl carried the missense (c.1153A-C (NM_130797) transversion, M385L). The same mutation was identified in her affected mother, aunt and grandfather. Patient BY0712 harboured a 336 kb deletion. Patient BY2018 harbored a362 kb deletion.

Created: 27 Feb 2017, 2:44 p.m.

DPP6 is on the Expert list for MCPH (primary microcephaly) from Andrew Jackson but with the caution that only a single mutation or family is reported in the literature.

Created: 13 Dec 2016, 12:11 p.m.