Noonan Syndrome via the A2ML1 Gene

Noonan Syndrome (NS) is characterized by dysmorphic facial features, growth and congenital heart defects, and musculoskeletal abnormalities. Cardiac abnormalities are found in up to 80% of patients and include pulmonary valve stenosis, atrial septal defect, atrioventricular canal defect, and hypertrophic cardiomyopathy. Musculoskeletal abnormalities include short stature, chest deformity with sunken or raised sternum, and short webbed neck. Several additional abnormalities have been described and include renal, genital, hematological, neurologic, cognitive, behavioral, gastrointestinal, dental, and lymphatic findings. Intelligence is usually normal; however, learning disabilities may be present. NS is characterized by extensive clinical heterogeneity, even among members of the same family. Diagnosis is often made in infancy or early childhood. Symptoms often change and lessen with advancing age. Infants with NS are at risk of developing juvenile myelomonocytic leukemia (JMML). The prevalence of NS is estimated at 1 in 1,000 to 1 in 2,500 births worldwide (Allanson. 1987. PubMed ID: 3543368; Romano et al. 2010. PubMed ID: 20876176; Smpokou et al. 2012. PubMed ID: 23165751; Cao et al. 2017. PubMed ID: 28643916).

Clinical features of Noonan syndrome overlap with those of Cardio-Facio-Cutaneous syndrome (Gripp et al. 2007. PubMed ID: 17551924; Rauen 2016. PubMed ID: 20301365), and Costello syndrome (Gripp and Lin. 2012. PubMed ID: 20301680).

Noonan and Noonan-like syndromes are caused by pathogenic variants in PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, NRAS, CBL, KAT6B, RIT1, SOS2, LZTR1, MAP3K8, SPRY1, NF1, RRAS, RASA2, and A2ML1 (Human Gene Mutation Database).

Pathogenic variants in the A2ML1 gene have been identified in patients presenting with features within the Noonan-spectrum disorders. Clinical features include broad and high forehead, hypertelorism, low set and posteriorly rotated ears, webbed neck, pulmonary valve stenosis, broad thorax, pectus excavaum, short stature, pigmented naevi, esy bruising, prenatal polydydramnios, intellectual disability and hearing loss (Vissers et al. 2015. PubMed ID: 24939586).

To date, three pathogenic missense variants in the A2ML1 gene have been identified, via whole exome sequencing, in patients with Noonan syndrome (Vissers et al. 2015. PubMed ID: 24939586). Evidence for pathogenicity include: (1) de novo origin of one variant in the sporadic case and co-segregation of two variants with the phenotype in the familial cases; (2) Functional characterization of the missense variants in zebrafish led to abnormalities similar to those seen in Noonan syndrome, including cardiac malformations, a broad head, and blunted face.

The A2ML1 gene encodes the secreted protease inhibitor α-2-macroglobulin-like-1, capable of activating the MAPK cascade (Galliano et al. 2006. PubMed ID: 16298998; Justino et al. 2015. PubMed ID: 24896146). It has been hypothesized that A2ML1 may act upstream of the signaling pathways that have been implicated in Noonan spectrum disorders (Vissers et al. 2015. PubMed ID: 24939586).

Pathogenic variants in the A2ML1 gene appear to be a rare cause of Noonan syndrome. They are expected to account for less than 0.5 % of patients clinically diagnosed with a Noonan spectrum disorder (Vissers et al. 2015. PubMed ID: 24939586).

This test provides full coverage of all coding exons of the A2ML1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.