Table 1.

Molecular Genetic Testing Used in MPPH Syndrome

Gene 1Number of Persons w/Molecularly Confirmed MPPH Syndrome Attributed to a Pathogenic Variant in Gene 2Number of Pathogenic Variants 3 Detectable by Method
Sequence analysis 4CMA 5
AKT3 ~30%50%50% 6
CCND2 ~30%100%NA
PIK3R2 ~40%100% 7, 8NA
1.
2.

References for the 41 individuals with a molecularly confirmed diagnosis: Mirzaa et al [2012], Poduri et al [2012], Rivière et al [2012], Wang et al [2013], Chung et al [2014], Jamuar et al [2014], Mirzaa et al [2014], Nakamura et al [2014], Tapper et al [2014], Conti et al [2015], Harada et al [2015], Nellist et al [2015], Hemming et al [2016], Terrone et al [2016]. Note that the other 23 individuals with a clinical diagnosis of MPPH syndrome did not undergo the complete molecular and cytogenetic testing required to detect the range of causative germline and somatic pathogenic variants.

3.

See Molecular Genetics for information on variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including AKT3) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 1q44 region. CMA designs in current clinical use target the 1q44 region.

6.

Duplications of 1q43-q44, which include AKT3, are detectable by CMA and cause macrocephaly and intellectual disability [Wang et al 2013, Chung et al 2014, Hemming et al 2016]. Somatic duplication of this locus has been identified in individuals with hemimegalencephaly and focal cortical dysplasia [Poduri et al 2012, Jamuar et al 2014, Conti et al 2015]. Although these large duplications would be detected by gene-targeted deletion/duplication assays, some methods would be unable to size the duplication.

7.

Mosaicism for a PIK3R2 pathogenic variant has been reported in individuals with MPPH syndrome [Mirzaa et al 2015].

8.

Most individuals with a PIK3R2 pathogenic variant have the same recurrent p.Gly373Arg variant. Only four other PIK3R2 pathogenic variants have been reported to date [Nakamura et al 2014, Mirzaa et al 2015, Terrone et al 2016].

From: MPPH Syndrome

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