Table 1.

Molecular Genetic Testing Used in Noonan Syndrome (NS)

Gene 1, 2Proportion of NS Attributed to Pathogenic Variants in GeneProportion of Probands with a Pathogenic Variant 3 Detected by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
BRAF <2% 6100%Unknown 7
KRAS <5% 8100%Unknown 7
LZTR1 ~8% 9100%Unknown 7
MAP2K1 <2% 10100%Unknown 7
MRAS <1% 11100%Unknown 7
NRAS <1% 12100%Unknown 7
PTPN11 50% 13Nearly 100%Rare duplication, 14 diagnosis of NS questioned 15
RAF1 5% 16Nearly 100%1 reported case w/a duplication, 17 diagnosis of NS questioned 15; 1 reported case of a deletion 18
RASA2 Unknown 19100%Unknown 7
RIT1 5% 16100%Unknown 7
RRAS2 <1% 20100%Unknown 7
SOS1 10%-13% 21100%Unknown 7
SOS2 ~4% 22100%Unknown 7
Others 23NA
1.

Genes are listed in alphabetic order.

2.

See Table A. Genes and Databases for chromosome locus and protein

3.

See Molecular Genetics for information on variants detected in these genes

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.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.
7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.

Approximately 16%-20% of individuals with a clinical diagnosis of Noonan syndrome who do not have an identified PTPN11 pathogenic variant are found to have an SOS1 pathogenic variant [Roberts et al 2007, Tartaglia et al 2007].

22.
23.

Recent reports have implicated additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals each, including RRAS (2 probands) [Flex et al 2014] and A2ML1 (3 probands) [Vissers et al 2015].

From: Noonan Syndrome

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