Noonan Spectrum Disorders Panel

Ordering Indications

Confirm a suspected clinical diagnosis of:

  • Noonan syndrome (NS)
  • Cardiofacial cutaneous syndrome (CFCS)
  • Costello syndrome (CS)
  • Legius syndrome (LS)
  • Noonan syndrome with multiple lentigines (LEOPARD syndrome)
  • Noonan-like syndrome
  • Noonan-like syndrome with loose anagen hair (NS/LAH)
Contraindications

This panel should not be ordered in individuals with primary JMML as the assay may not detect mosaicism for somatic variants associated with malignancy.

Testing Strategy

Given the genotypic and phenotypic overlap among Noonan spectrum disorders (NSDs), the NSD panel is the recommended first-line test for determining a genetic etiology. 

Ordering Indications

Confirm a diagnosis of a NSD in a pregnancy with clinically suggestive findings, such as increased nuchal translucency, cystic hygroma, and cardiac defects.

Testing Strategy

For a fetus with ultrasonographic abnormalities, genomic microarray should be ordered prior to the NSD panel. 

Noonan spectrum disorders (NSD) are a group of genetic syndromes caused by pathogenic germline variants in genes in the Ras/mitogen activated protein kinase (MAPK) pathway, which controls the cell cycle and cell differentiation. The vast majority of causative variants increase pathway signaling; thus, the resulting syndromes exhibit phenotypic overlap and share a predisposition for developing malignancies.

Disease Overview

Symptoms of Noonan Syndrome (NS)

  • Characteristic facial features
  • Short stature
  • Broad webbed neck (fetal cystic hygroma/increased nuchal translucency)
  • Congenital heart defect
  • Developmental delay
  • Undescended testes
  • Coagulation defects
  • Lymphatic dysplasias

Etiology of NSDs

Pathogenic sequence variants in Ras pathway genes

Prevalence

NS – 1/1,000-2,500

Inheritance

Autosomal dominant for all analyzed genes

Genotype-Phenotype Correlation

Variants in multiple genes cause overlapping phenotypes for NSD

Test Description

See Genes Tested table for genes included in this panel.

Clinical Sensitivity

Dependent on clinical phenotype

Limitations

  • A negative result does not exclude a diagnosis of a MAPK pathway disorder.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Large deletions/duplications
    • Noncoding transcripts
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants

Analytic Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene Alias Symbol(s) MIM Number Disorder

BRAF

BRAF1

164757

CFCS 1

NS 1

NS 7

LEOPARD syndrome 3

CBL

CBL2, RNF55, c-Cbl

165360

NS-like disorder with or without juvenile myelomonocytic

HRAS

HRAS1

190020

Melanocytic Nevus syndrome, congenital

Schimmelpenning-Feuerstein-Mims syndrome

CS

KRAS

KRAS2, KRAS1

190070

Schimmelpenning-Feuerstein-Mims syndrome

NS 3

CFCS 2

LZTR1

LZTR-1, BTBD29

600574

NS 10

MAP2K1

PRKMK1, MEK1, MAPKK1

176872

NS 1

CFCS 3

MAP2K2

PRKMK2, MEK2

601263

CFCS 4

NRAS

N-ras

164790

Schimmelpenning-Feuerstein-Mims syndrome

NS 6

PTPN11

NS1, BPTP3, SH-PTP2, SHP-2, PTP2C, SHP2

176876

LEOPARD syndrome 1

NS 1

RAF1

Raf-1, c-Raf, CRAF

164760

NS 5

LEOPARD syndrome 2

RASA2

GAP1M

601589

 

RIT1

RIT, RIBB, ROC1, MGC125864, MGC125865

609591

NS 8

SHOC2

KIAA0862, SOC2, SUR-8, SOC-2, SUR8

602775

NS-like disorder with loose anagen hair 1

SOS1

GINGF, HGF, GF1

182530

NS 4

SOS2

 

601247

NS 9

SPRED1

FLJ33903, PPP1R147

609291

Legius syndrome

References