The Invitae Noonan Syndrome with Multiple Lentigines Panel analyzes three genes associated with Noonan syndrome with multiple lentigines (NSML)—formerly known as LEOPARD syndrome. NSML is one of the RASopathies, which are a class of pediatric disorders associated with genes that are members of the mitogen-activated protein kinase (Ras/MAPK) pathway. This pathway is involved in a signal transduction cascade that is necessary for the proper formation of several types of tissue during embryonic and postnatal development.
NSML is characterized by lentigines, café-au-lait macules, hearing loss, congenital heart defects (pulmonary valve stenosis), short stature, and increased risk of malignancies; however, the RASopathies have several overlapping phenotypic features due to their common underlying Ras/MAPK pathway dysregulation.
This test can help clinicians make a definitive diagnosis in a patient with a suspected RASopathy disorder. If the underlying genetic cause is identified, a patient can be monitored and managed appropriately for the symptoms that are specific to that syndrome. Additionally, by determining the patient’s specific pathogenic variant, additional family members can then be tested. A molecular diagnosis is particularly important due to the variable expressivity of NSML. In certain patients, symptoms may be mild and a clinical diagnosis is not readily apparent.
BRAF PTPN11 RAF1
BRAF PTPN11 RAF1
The RASopathies are multisystemic disorders whose expressions are highly variable, even among family members. Many of the clinical features that can differentiate RASopathy conditions manifest later in childhood or change with age, making accurate clinical diagnosis difficult. The phenotypes of many RASopathy conditions are expanding: Individuals are being discovered with a molecular genetic finding in a RASopathy gene but clinical findings that are not typically described in the specific condition associated with that gene. Additionally, some genes are associated with more than one RASopathy syndrome.
Testing for NSML is also included in the broader Invitae RASopathies Comprehensive Panel. Depending on the individual’s clinical and family history, this broader panel may be appropriate. This broader panel can be ordered at no additional charge.
Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is a pediatric disorder that affects multiple organ systems. LEOPARD is a mnemonic for the cardinal symptoms of individuals with this disorder:
Additional symptoms may include cognitive deficiencies, pectus deformity, skeletal abnormalities, and café-au-lait spots. Lentigines typically do not appear on the patient until around age four or five years; then, the number of lentigines steadily increases to the thousands by the time the patient has reached puberty. Some individuals, though, never develop lentigines. Approximately 85% of patients have heart defects including hypertrophic cardiomyopathy and pulmonary valve stenosis. Approximately 50% of patients show postnatal growth retardation, with heights within only the 25th percentile for age. Intellectual disability is present in approximately 30% of patients and is typically mild. Sensorineural hearing loss is observed in approximately 20% of patients. Typical facial features include widely spaced eyes and ptosis.
A disease causing variant is typically found in approximately 95% of patients with a clinical diagnosis of NSML. 90% of those variants are found in the PTPN11 gene. Approximately 5% of variants are found in the RAF1 gene. To date, only two individuals with NSML have been found with a pathogenic variant in the BRAF gene.
NSML is inherited in an autosomal dominant pattern.
Penetrance of this syndrome is difficult to determine due its variable expressivity. Patients are typically diagnosed in childhood, though some adults with more subtle features are not diagnosed until they have a child who presents with a more severe phenotype.
The prevalence of NSML in the general population is unknown. Only approximately 200 cases have been reported.
Testing for NSML should be considered when presented with a patient who has multiple lentigines and two of the other cardinal features (cardiac abnormalities, short stature/poor growth, pectus deformity, and dysmorphic facial features). Testing should also be considered if three cardinal features are present in a patient with a first-degree relative with NSML.
For management recommendations, please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|