Severe microcephaly

Gene: ZNF335

The mode of inheritance of this gene has been updated to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 26 Sep 2024, 3:20 p.m. | Last Modified: 26 Sep 2024, 3:20 p.m.

Panel Version: 6.6

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on mode of inheritance: Other than the one case that was reported by Chicago lab with ZNF335 heterozygous variant (c.2515_2518dupGCCA/ p.Thr840Serfs) and with microcephaly, encephalopathy and developmental delay, all other cases reported in the literature and ClinVar had biallelic variants in ZNF335. Hence, the MOI should be updated to "BIALLELIC, autosomal or pseudoautosomal" in the next GMS review.

Created: 21 Feb 2024, 8:40 p.m. | Last Modified: 21 Feb 2024, 8:40 p.m.

Panel Version: 4.60

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

NO evidence for being BOTH monoallelic and biallelic. Should be changed to biallelic only.

Created: 25 Jan 2024, 12:06 p.m. | Last Modified: 25 Jan 2024, 12:06 p.m.

Panel Version: 4.53

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

Created: 10 Mar 2022, 10:52 a.m. | Last Modified: 10 Mar 2022, 10:52 a.m.

Panel Version: 2.282

Green List (high evidence)

Comment on list classification: There is enough evidence for this gene to be rated Green at the next GMS panel update (added 'for-review' tag).

Created: 27 Oct 2020, 12:12 p.m. | Last Modified: 27 Oct 2020, 12:12 p.m.

Panel Version: 2.34

Associated with relevant phenotype in OMIM, but currently not in Gene2Phenotype.

At least 6 unrelated families reported in literature with different biallelic variants in ZNF335. All affected individuals present with severe congenital or acquired microcephaly (OFC < -3SD), with the exception of one less severely affected case (patient B from PMID:29652087), in whom head circumference at 3 months was −1.22 SD. Functional analyses have corroborated implication in this phenotype, including a supportive animal model.

Created: 27 Oct 2020, 12:11 p.m. | Last Modified: 27 Oct 2020, 12:11 p.m.

Panel Version: 2.33

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly 10, primary, autosomal recessive, 615095

Publications

• 23178126
• 27540107
• 29652087
• 30500859
• 31187448

Green List (high evidence)

At least 3 unrelated individuals with severe microcephaly (-3.24SD, -5SD, -9SD). Variants are all missense or in-frame del.

Created: 31 Aug 2020, 6:51 a.m. | Last Modified: 31 Aug 2020, 6:51 a.m.

Panel Version: 2.19

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly 10, primary, autosomal recessive (MIM#615095)

Publications

• 23178126
• 27540107
• 29652087

Variants in this GENE are reported as part of current diagnostic practice

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 only enough evidence to rate this gene Amber

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

Panel Version: 1.62

Comment on mode of inheritance: Changed MOI from 'biallelic' to 'both monoallelic and biallelic' based on information from Chicago University about ClinVar variant c.2515_2518dupGCCA (p.Thr840Serfs).

Created: 1 Mar 2017, 10:09 a.m.

Comment on list classification: Updated rating from Red to Amber: 1 published case plus 1 case in-press plus mouse model. Changed rating to Amber until the Baylor lab paper at least is published, and more information is available about additional variants.

Created: 1 Mar 2017, 10:03 a.m.

1 further 'likely pathogenic' variant submitted to ClinVar by Chicago lab, under 'Primary autosomal recessive microcephaly 10':
NM_022095.3(ZNF335):c.2515_2518dupGCCA (p.Thr840Serfs)
The lab confirmed that they saw this variant in one patient, who was reported to have microcephaly, encephalopathy and developmental delay. The variant was heterozygous, and no second variant was found by either sequencing or deletion/duplication studies.

Created: 1 Mar 2017, 10:01 a.m.

2 further 'Pathogenic' variants submitted to ClinVar by Baylor, under 'Primary autosomal recessive microcephaly 10':
NM_022095.3(ZNF335):c.3787G>T (p.Glu1263Ter)
NM_022095.3(ZNF335):c.2744_2747delGTGA (p.Ser915Thrfs)
Correspondance with the Baylor lab revealed that the proband's phenotype was developmental delay, intellectual disability, seizures, hypomyelination, failure to thrive. A paper is currently in press in Genome Medicine.

Created: 1 Mar 2017, 10:01 a.m.

1 case in literature/OMIM: PMID:23178126 (Yang et al., 2012) identify 3332G-A (ARG1111HIS) in affected members of an Arab Israeli family. PMID:26479514 (Nishida et al., 2016) discuss anaesthesia in a female patient with MCPH-10 and a ZNF335 gene mutation, but don't discuss the mutation in further detail.

Created: 28 Feb 2017, 11:48 a.m.

I don't know

Mutations only identified in one family but supported by mouse model

Created: 12 Jan 2017, 11:16 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Microcephaly 10, primary, autosomal recessive 615095

Publications

• 23178126