Severe microcephaly

Gene: TMEM161B

Green List (high evidence)

Comment on list classification: There are 5 probands reported in literature with 3 unique sets of biallelic TMEM161B variants and a syndromic neurological disorder including severe microcephaly. Hence, this gene can be promoted to Green.

Created: 3 Nov 2026, 2:29 p.m. | Last Modified: 3 Nov 2026, 2:29 p.m.

Panel Version: 9.60

PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported; it is not known if probands with the same variants are related, so best to score as 2 independent families. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound. All individuals had seizures, with onset in the first few months of life. No cardiovascular abnormalities, no ophthalmic features apart from megalocornea in 1 family.

PMID: 36669111 Akula et al., 2023
Study describes 3 families with probands either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8).
Individual 09DG00538, Family A - presented at birth after normal delivery with intractable seizures, severe microcephaly, and hypotonia/spastic paresis; an MRI revealed diffuse PMG.
Individual UDN172478, Family B- diffuse PMG, pachygyria. Head circumference unknown.
4 sibs in Family C - presented with spastic hemiparesis, dysarthria, intellectual disability, and seizures. Diffuse PMG was discovered in the eldest sibling on autopsy; brain imaging unavailable for other sibs. HC measurements unknown.

Article also generated and described TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes).
Sources: Literature

Created: 3 Nov 2026, 12:18 p.m. | Last Modified: 3 Nov 2026, 2:30 p.m.

Panel Version: 9.60

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
polymicrogyria, MONDO:0000087; microcephaly, MONDO:0001149

Publications

• 36669109
• 36669111
• 38593811
• 37486637