Severe microcephaly

Gene: PUF60

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

Created: 10 Mar 2022, 1:37 p.m. | Last Modified: 10 Mar 2022, 1:37 p.m.

Panel Version: 2.292

Green List (high evidence)

Comment on list classification: Promoting from grey to amber but with a recommendation for green rating at the next GMS review. 3 cases reported with heterozygous variants in PUF60 and a severe microcephaly phenotype.

Created: 19 May 2021, 3:51 p.m. | Last Modified: 19 May 2021, 3:51 p.m.

Panel Version: 2.176

Associated with Verheij syndrome #615583 (AD) in OMIM with microcephaly listed as a clinical feature.

23 patients with heterozygous variants in PUF60 reported, 3 with severe microcephaly.

PMID: 24140112 - Dauber et al 2013 - report a 21 year old female with a de novo heterozygous variant in PUF60 (c.505C>T;p.His169Tyr) with developmental delay, microcephaly, and craniofacial and cardiac defects. At age 20 her head circumference was −4.1 SD. They also report 5 individuals with 8q24.3 deletions that cover PUF60 and 2 other genes. Microcephaly reported in 3, but not in the severe range.

PMID: 27804958 - El Chehadeh et al 2017 - report 5 unrelated patients with de novo heterozygous protein altering variants in PUF60 found by WES. Only one had a microcephaly phenotype but this was severe (−3.2 SD at age 3 weeks)

PMID: 28327570- Low et al 2017 - report 12 patients with VRJS who had de novo heterozygous variants in PUF60 found by WES. Microcephaly was noted in 5 patients who had the following Z-scores (−2.48, −4.22, −2.09, −2.99, −2.53 respectively). Using a Z-score of -3 as the cut-off for severe microcephaly, this means one of the patients falls into this category and another one very close.

PMID: 28074499 - Santos-Simarro et al. 2017 - report 3 further patients with de novo heterozygous variants in PUF60 and a phenotype that includes developmental delay and growth retardation but no severe microcephaly reported.

PMID: 28471317 - Graziano et al 2018 - report a boy with a de novo heterozygous missense variant in PUF60 (same variant as reported by Santos-Simaro) who has a complex eye development and multisystem phenotype. Microcephaly is not reported.

PMID: 32851780 - Yamada et al 2020 - report a girl with a mild phenotype that does not include microcephaly and a de novo heterozygous frameshift variant in PUF60 leading to the addition of 21 extra amino acids at the carboxy end of the protein

Created: 19 May 2021, 3:50 p.m. | Last Modified: 19 May 2021, 3:50 p.m.

Panel Version: 2.173

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Verheij syndrome, OMIM:615583

Publications

• 24140112
• 27804958
• 28327570
• 28074499
• 28471317
• 32851780

Green List (high evidence)

Over 15 affected individuals reported. Short stature and dev delay are consistent features. 5/12 in the largest case series had microcephaly in relation to stature (Z-scores −2.48, −4.22, −2.09, −2.99, −2.53 respectively).
Sources: Expert list

Created: 3 Sep 2020, 3:30 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Verheij syndrome, MIM# 615583

Publications

• 28327570

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