Cardiac Findings in Noonan Syndrome on Long-term Follow-up

Colquitt, John L.; Noonan, Jacqueline A.

doi:10.1111/chd.12102

Cited by 60 publications

(52 citation statements)

References 21 publications

(47 reference statements)

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“…Of note, phenotypic variability is well known for NS, and more explicitly, not all patients with NS have a cardiac malformation. 5,25 Also, the affected individuals in the two families with an A2ML1 mutation do not have a heart defect, while the same mutations in zebrafish cause cardiac malformation. Zebrafish mutants of the most recently described NS gene, RIT1, show incomplete looping of the heart and hypoplastic heart chambers, whereas the heart phenotype was variable or even absent in patients with RIT1 mutations.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4] Congenital heart defects are observed in a large proportion of NS patients, in particular pulmonary stenosis (66%), and hypertrophic cardiomyopathy (14%). 5 Other relatively frequent clinical features of NS patients include webbed neck, cryptorchidism, bleeding tendency and hydrops fetalis. NS is genetically heterogeneous and mutations in PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, CBL and RIT1 account for approximately 75% of affected individuals.…”

Section: Introductionmentioning

confidence: 99%

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Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome

et al. 2014

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Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphisms and congenital heart defects. To date, all mutations known to cause NS are dominant, activating mutations in signal transducers of the RAS/ mitogen-activated protein kinase (MAPK) pathway. In 25% of cases, however, the genetic cause of NS remains elusive, suggesting that factors other than those involved in the canonical RAS/MAPK pathway may also have a role. Here, we used family-based whole exome sequencing of a case-parent trio and identified a de novo mutation, p.(Arg802His), in A2ML1, which encodes the secreted protease inhibitor a-2-macroglobulin (A2M)-like-1. Subsequent resequencing of A2ML1 in 155 cases with a clinical diagnosis of NS led to the identification of additional mutations in two families, p.(Arg802Leu) and p.(Arg592Leu). Functional characterization of these human A2ML1 mutations in zebrafish showed NS-like developmental defects, including a broad head, blunted face and cardiac malformations. Using the crystal structure of A2M, which is highly homologous to A2ML1, we identified the intramolecular interaction partner of p.Arg802. Mutation of this residue, p.Glu906, induced similar developmental defects in zebrafish, strengthening our conclusion that mutations in A2ML1 cause a disorder clinically related to NS. This is the first report of the involvement of an extracellular factor in a disorder clinically related to RASopathies, providing potential new leads for better understanding of the molecular basis of this family of developmental diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome

et al. 2014

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“…HCM is also distinct from other genetic diseases that can cause LV hypertrophy in humans, especially in childhood, such as Noonan syndrome or Danon’s disease. 5,6,7 …”

Section: Human Hcmmentioning

confidence: 99%

The genetic basis of hypertrophic cardiomyopathy in cats and humans

Kittleson

Meurs

Harris

2015

Journal of Veterinary Cardiology

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“…With respect to cardiac risk, Pierpont et al (2009) did not find a significant association between heart disease severity ratings and verbal or nonverbal cognitive abilities in a relatively large sample of children with NS. While congenital heart disease is known to confer risk for neurocognitive deficits, intellectual impairments are most frequently seen for cyanotic conditions or those requiring open heart surgery in the neonatal period (Marino et al 2012), which occur in a relatively small percentage of children with NS (Colquitt and Noonan 2014). For individuals with NS who have more severe cardiac conditions requiring surgery, no studies have examined whether specific operative or postoperative factors may give rise to differences in cognition or behavior.…”

Section: Intellectual Functioningmentioning

confidence: 99%

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

Pierpont

2015

J Pediatr Neuropsychol

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Noonan syndrome (NS) is a relatively common genetic syndrome with variable features including short stature, congenital heart disease, distinctive facial characteristics, skeletal anomalies, and varying degrees of developmental delay. NS is caused by gene mutations in a cellular signaling pathway that is essential for typical growth and development. Research in the past few decades has revealed that individuals with NS have highly variable neurocognitive and behavioral outcomes. To a certain extent, variability in cognitive functioning depends on the particular gene where a mutation is found; additionally, factors related to medical severity and environmental effects contribute substantially to outcomes. This article contains a systematic review of research on neuropsychological features of NS, including cognition, motor development, language, memory, attention, visual perception, adaptive behavior, social skills, and mental health concerns. Given the wide variety of possible cognitive and behavioral complications associated with NS, it is recommended that clinical neuropsychological evaluation of cognitive, adaptive, and psychological domains of functioning should be standard of care for all individuals with NS. Suggested considerations for assessment of individuals with NS are provided. The paper concludes with recommendations for educational and therapeutic interventions, as well as suggestions for future research directions.

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Cardiac Findings in Noonan Syndrome on Long-term Follow-up

Cited by 60 publications

References 21 publications

Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome

Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome

The genetic basis of hypertrophic cardiomyopathy in cats and humans

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

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