Severe microcephaly

Gene: SASS6

Green List (high evidence)

Comment on list classification: As reviewed by Zornitza Stark, there are two additional unrelated cases reported with severe microcephaly (HC was beyond -4 SD in both cases). Hence, this gene can be promoted to green rating in the next GMS update.

Created: 26 Jun 2024, 4:22 p.m. | Last Modified: 26 Jun 2024, 4:22 p.m.

Panel Version: 5.15

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly 14, primary, autosomal recessive, OMIM:616402

Green List (high evidence)

The rating of this gene has been updated to green 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

Comment on list classification: Promoting from red to amber as now two cases reported with severe microcephaly. Pubmed search did not find further cases at this time.

Created: 20 May 2021, 10:28 a.m. | Last Modified: 20 May 2021, 10:28 a.m.

Panel Version: 2.182

Provisionally associated with ?Microcephaly 14, primary, autosomal recessive #616402 (AR) in OMIM.

PMID: 24951542 - Khan et al 2014 - large consanguineous Pakistani family with 4 patients diagnosed with autosomal recessive primary microcephaly (MCPH). Sequencing of genes following homozygosity mapping identified a homozygous missense variant in HsSAS-6 (c.185T>C, p.Ile62Thr ). Analysed unaffected individuals were either heterozygous for this variant, or had two wild type alleles. All 4 affected individuals had severe microcephaly (occipitofrontal circumference ranged from -6.63 to -19.6 SD).

PMID: 30639237 - Zhang et al 2019 - report a non-consanguineous Chinese family in which two foetuses were identified with microcephaly. In the later pregnancy the foetus had a head circumference -4 SD at 24 weeks of gestation. Compound heterozygous splice variants in SASS6 were identified by WES ( c.127-13A>G and c.1867+2T>A), one inherited from each of the parents. RT-PCR confirmed the effect on splicing.

Created: 20 May 2021, 10:25 a.m. | Last Modified: 20 May 2021, 10:26 a.m.

Panel Version: 2.180

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Microcephaly 14, primary, autosomal recessive, OMIM:616402

Publications

• 24951542
• 30639237

Green List (high evidence)

Two additional families:

PMID: 38501757
1x compound het for a fs and +3 splice variant.

Using cDNA RT-ed from mother's RNA, exons 13-15 were amplified and exon 14 was found to be skipped resulting in c.1546_1674del and p.516_558del

PMID: 36739862
1x family, compound het for 2 missense
Functional studies not performed

Created: 22 Apr 2024, 8:26 a.m. | Last Modified: 22 Apr 2024, 8:26 a.m.

Panel Version: 4.67

Second family reported.

Created: 3 Sep 2020, 8:04 a.m. | Last Modified: 3 Sep 2020, 8:04 a.m.

Panel Version: 2.20

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly 14, primary, autosomal recessive, MIM# 616402

Publications

• 24951542
• 30639237
• 38501757
• 36739862

I don't know

As discussed with the GMS Neurology Specialist Test Group webex call 11thJuly 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Red

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

Panel Version: 1.62

PMID:24951542 (Khan et al., 2014) examined three affected individuals from a consanguineous MCPH family from Pakistan and identified a homozygous c.185T>C missense mutation in the SASS6 gene, resulting in a p.Ile62Thr substitution. The Ile62Thr mutant of SASS6 is substantially less efficient than the wild-type protein in sustaining centriole formation.

Created: 13 Dec 2016, 10:55 a.m.