Assessing the Gene-Disease Association of 19 Genes with the RASopathies using the ClinGen Gene Curation Framework

Grant, Andrew R.; Cushman, Brandon J.; Cavé, Hélène; Dillon, Mitchell W.; Gelb, Bruce D.; Gripp, Karen W.; Lee, Jennifer A.; Mason‐Suares, Heather; Vincent, Lisa M.; Zenker, Martin

doi:10.1101/323303

Cited by 27 publications

(39 citation statements)

References 28 publications

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“…The identification of a known CS‐associated germline HRAS mutation confirms the diagnosis of CS and may clarify the diagnosis in individuals whose phenotype overlaps with other RASopathies. For novel variants, a careful review and validation is necessary (Grant et al, ). Molecular confirmation of the clinical diagnosis assists in clarifying risks based upon genotype–phenotype correlations (Table ).…”

Section: Molecular Geneticsmentioning

confidence: 99%

Costello syndrome: Clinical phenotype, genotype, and management guidelines

Gripp

Morse

Axelrad

et al. 2019

American J of Med Genetics Pt A

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102

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Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues;however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are

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Section: Molecular Geneticsmentioning

confidence: 99%

Costello syndrome: Clinical phenotype, genotype, and management guidelines

Gripp

Morse

Axelrad

et al. 2019

American J of Med Genetics Pt A

Self Cite

102

111

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“…In addition, there are emerging genes (e.g. , RASA2, PPP1CB, and SOS2) with limited to strong association to RASopathy‐associated pathognomonic features, as well as LZTR1 , which is associated with a dominant and recessive form of disease (Grant et al, ).…”

Section: Introductionmentioning

confidence: 99%

Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1

Witkowski

Dillon

Murphy

et al. 2020

Molec Gen & Gen Med

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Background:RASopathies are a group of disorders caused by disruptions to the RAS-MAPK pathway. Despite being in the same pathway, Neurofibromatosis Type 1 (NF1) and Legius syndrome (LS) typically present with phenotypes distinct from Noonan spectrum disorders (NSDs). However, some NF1/LS individuals also exhibit NSD phenotypes, often referred to as Neurofibromatosis-Noonan syndrome (NFNS), and may be mistakenly evaluated for NSDs, delaying diagnosis, and affecting patient management. Methods: A derivation cohort of 28 patients with a prior negative NSD panel and either NFNS or a suspicion of NSD and café-au-lait spots underwent NF1 and SPRED1 sequencing. To further determine the utility and burden of adding these genes, a validation cohort of 505 patients with a suspected RASopathy were tested on a 14-gene RASopathy-associated panel. Results:In the derivation cohort, six (21%) patients had disease-causing NF1 or SPRED1 variants. In the validation cohort, 11 (2%) patients had disease-causing variants and 15 (3%) had variants of uncertain significance in NF1 or SPRED1. Of those with disease-causing variants, 5/17 only had an NSD diagnosis. Conclusions: Adding NF1 and SPRED1 to RASopathy panels can speed diagnosis and improve patient management, without significantly increasing the burden of inconclusive results.

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“…These include KRAS, SOS1, RAF1, NRAS, BRAF, RIT1 and SOS2. 7 Despite these gene discovery efforts, a small but significant fraction of cases remain mutation-negative for known genes.…”

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confidence: 99%

Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

et al. 2019

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Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1‐ associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly‐acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound‐heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss‐of‐function mutations in NEB , consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities ( P = 0.0005), supporting a causal role for LZTR1 . Second, targeted sequencing of eight unsolved NS‐like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.‐38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1‐4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.

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Assessing the Gene-Disease Association of 19 Genes with the RASopathies using the ClinGen Gene Curation Framework

Cited by 27 publications

References 28 publications

Costello syndrome: Clinical phenotype, genotype, and management guidelines

Costello syndrome: Clinical phenotype, genotype, and management guidelines

Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1

Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

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