Severe microcephaly

Gene: RBBP8

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: 3 unrelated cases of variants of Seckel syndrome (MIM:606744) or Jawad syndrome (MIM:251255). Plus an additional 2015 case PMID:26333564 that may or may not represent a related family. Additional evidence comes from PMID:24440292 where NRXN1 may also be involved.

Created: 2 Mar 2017, 9:27 a.m.

PMID:24440292 (Agha et al., 2014) report a consanguineous Pakistani family with severe congenital micropcephaly in 2 affected brothers. The brothers carried the c.919A>G, p.Arg307Gly mutation. The brothers and their mother (mildly affected) also carried a heterozygous 607kb deletion encompassing exons 13-19 of NRXN1.

Created: 28 Feb 2017, 10:29 a.m.

PMID:26333564 (Mumtaz et al., 2015) report on a consanguineous Pakistani family with homozygous RBBP8 mutation c.1808_1809delTA (rs587776884, p.Ile603Lysfs*7) in at least 4 affected siblings (2 males, 2 females) manifesting microcephaly (amongst other symptoms). This is the same mutation as reported in the Pakistani family examined by Qvist et al., 2011 (PMID:21998596) so it is unclear if this represents a separate case like the authors suggest.

Created: 28 Feb 2017, 10:29 a.m.

In a 9 year old Saudi Arabian girl with Seckel syndrome-2, Shaheen et al. 2014 (PMID:24389050) identified homozygosity for a
c.298C-T transition (R100W) in RBBP8.

Created: 28 Feb 2017, 9:54 a.m.

Qvist et al., 2011 (PMID:21998596) examined 2 unrelated microcephalic families- an Iraqi family with Seckel syndrome-2 (MIM:606744) and a Pakistani family with Jawad syndrome (MIM:251255). They identified a homozygous splice site mutation in 4 affected sibs from consanguineous Iraqi family with Seckel syndrome-2; Unaffected parents were both heterozygous and the mutation was not found in 100 controls. The mutation acts as a dominant negative. In the consanguineous Pakistani family with Jawad syndrome, Qvist identified a 2bp homozygous deletion in RBBP8 causing frameshift and premature termination; the mutation was heterozygous in carriers and not found in controls.

Created: 28 Feb 2017, 9:53 a.m.

I don't know

Mutations identified in one family and one individual with Seckel

Created: 11 Jan 2017, 3:04 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Seckel syndrome 2 606744

Publications

• 21998596
• 24389050