Noonan Spectrum Disorders Panel

Last Literature Review: February 2019 Last Update:

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)

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

Contraindications: This panel should not be ordered in individuals with primary juvenile myelomonocytic leukemia (JMML) as the assay may not detect mosaicism for somatic variants associated with malignancy.

Confirm a diagnosis of an NSD in a pregnancy with clinically suggestive findings, such as increased nuchal translucency, cystic hygroma, and cardiac defects. For a fetus with ultrasonographic abnormalities, genomic microarray should be ordered prior to the NSD panel.

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Noonan spectrum disorders (NSDs) 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

  • Approximately 99% for cardiofaciocutaneous syndrome (CFCS) 
  • Approximately 80-90% for Costello syndrome (CS)    
  • Approximately 70-80% for NS - 

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 Analytic Sensitivity (PPA) Estimatea (%) Analytic 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