Severe microcephaly

Gene: MED17

I don't know

Comment on list classification: There are 4 unrelated families (Jewish families with potential founder variant counted as one) where individuals had progressive microcephaly and harboured biallelic MED17 variants. However, only the Jewish patients in PMID 20950787 met the severity criteria of HC more severe than -3SD or <0.4 percentile. Other cases were -2SD for age, and 'under 3rd percentile'. Hence, this gene can only be rated Amber until more evidence emerges.

Created: 22 Jun 2026, 10:28 a.m. | Last Modified: 22 Jun 2026, 10:28 a.m.

Panel Version: 9.6

PMID 20950787 Kaufmann et al., 2010
Homozygous variant p.L371P was identified in 9 patients from 4 Caucasus Jewish families. Five infants from four unrelated families presented soon after birth with spasticity, epilepsy, and profound psychomotor retardation. Head circumference percentiles declined (HC −6 SD at 9 mo of age - avg for the group?), and brain MRI disclosed marked cereberal and cerebellar atrophy with severe myelination defect.

PMID: 26004231 Hirabayashi, Saitsu, & Matsumoto, 2016
2 sibs with nystagmus and sudden opistotonic posturing from the early infancy, developmental delay and marked choreiform movements with hypotonia in the childhood. The brother had a mild postnatal microcephaly (-2SD at 6 years) - no microcephaly in the sister. Brain MRI of the sister showed mild delay of myelination, dilated anterior horn and mild cerebellar atrophy. WES revealed comp het MED17 mutations in both: c.1013-5A>G, p. Ser338Asnfs*15 and c.1484T>G, p.Leu495Trp (in trans).

PMID: 30345598 Agostini et al., 2018
Report of two female siblings presenting with failure to thrive in early years, progressive microcephaly, moderate intellectual disability, developmental delay, ataxic gait and seizures with an identical EEG pattern, and minimal cerebellar atrophy. Both sibs were comp het for MED17: p.Glu16fs and p.Gly253Arg (confirmed in trans). Head circumference for both sibs was "below 3rd percentile" at age 10 years.

PMID: 36508181 Rafiullah et al., 2022
Consanguineous family with 2 individuals presenting with severe ID, seizure, and progressive microcephaly. Magnetic resonance imaging (MRI) of the brain showed mild brain atrophy and myelination defect. WES detected homozygous MED17 variant NM_004268.5_c.871T>C; p.Trp291Gly - confirmed het in unaffected parents and sibs. Head circumference was more than 2SD below the mean in both patients.

MED17 is associated with AR Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM:613668 (OMIM accessed 22nd Jun 2026).

Created: 22 Jun 2026, 10:23 a.m. | Last Modified: 22 Jun 2026, 10:23 a.m.

Panel Version: 9.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668

Publications

• 20950787
• 26004231
• 30345598
• 36508181

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. This gene as been given an Amber rating as 2 out of 3 cases (PMID:20950787 is caused by founder effect) have severe microcephaly. Until further evidence is available this gene will remain as Amber.

Created: 20 Sep 2021, 1:04 p.m. | Last Modified: 20 Sep 2021, 1:04 p.m.

Panel Version: 2.239

Green List (high evidence)

Five individuals from four families reported initially, founder effect for p.Leu371Pro. Two additional families reported since with different variants, one family with milder phenotype.
Sources: Expert list

Created: 31 Aug 2020, 6:27 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM# 613668

Publications

• 20950787
• 30345598
• 26004231

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