Severe microcephaly

Gene: AP4S1

Comment from NHS Genomic Medicine Service: primary presentation is ID/DD/spasticity/hypotonia: green on ID and HSP and hypotonic infant panels - not clear if severe microephaly exists in absence of these.

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

Panel Version: 2.282

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.

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

Panel Version: 2.282

Comment on list classification: New gene added by Zornitza Stark. Rating Amber with recommendation of review by the GMS team to assess whether there is sufficient evidence to support a Green rating (added 'for-review' tag)

Created: 27 Jan 2021, 4:59 p.m. | Last Modified: 27 Jan 2021, 4:59 p.m.

Panel Version: 2.88

Literature search revealed at least 23 individuals from 17 unrelated families reported in literature with biallelic variants in this gene (PMID: 21620353; 25552650; 27444738; 30283821; 32216065; 32979048). Microcephaly was observed in 15/21 cases but precise details regarding head circumference were mostly omitted or presentation was too mild relative to the scope of this panel. However, at least 2 individuals (2 families) did have microcephaly of relevant severity (OFC ≤ -3 SD) (see PMIDs: 21620353 and 25552650).

This disorder may be better represented by other panels (e.g. HSP, ID) for which this gene is already Green.

- PMID: 32216065 (2020) - Zebrafish model recapitulates several human phenotypes, including decreased head size.

Created: 27 Jan 2021, 4:58 p.m. | Last Modified: 27 Jan 2021, 5:02 p.m.

Panel Version: 2.88

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 21620353
• 25552650
• 27444738
• 30283821
• 32216065
• 32979048

Green List (high evidence)

Borderline Amber/Green as only one affected individual <-3SD; however, part of same gene family as other spastic paraplegias with microcephaly. Microcephaly in another family -2SD and precise information on the microcephaly not available for third family.
Sources: Expert list

Created: 31 Aug 2020, 11:06 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 52, autosomal recessive (MIM#614067)

Publications

• 21620353
• 25552650
• 27444738

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