Noonan syndrome‐like phenotype in a patient with heterozygous <scp><i>ERF</i></scp> truncating variant

Yamada, Mamiko; Funato, Michinori; Kondo, Goro; Suzuki, Hisato; Uehara, Tomoko; Tamura, Toshiki; Sakamoto, Yoshiaki; Kosaki, Kenjiro

doi:10.1111/cga.12435

Cited by 4 publications

(4 citation statements)

References 35 publications

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“…A large proportion of the patients with pathogenic ERF variants who display syndromic craniosynostosis have features that overlap with those of Noonan syndrome. Yamada et al (2021) reported a patient with a Noonan syndrome-like phenotype associated with an ERF truncating variant. Other previous reports of ERF-related disorders did not describe a Noonan syndrome-like phenotype, but in some patients, overlapping phenotypes were noted retrospectively (Chaudhry et al, 2015;Glass et al, 2019;Körberg et al, 2020;Moddemann et al, 2022;Twigg et al, 2013;Yamada et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Yamada et al (2021) reported a patient with a Noonan syndrome-like phenotype associated with an ERF truncating variant. Other previous reports of ERF-related disorders did not describe a Noonan syndrome-like phenotype, but in some patients, overlapping phenotypes were noted retrospectively (Chaudhry et al, 2015;Glass et al, 2019;Körberg et al, 2020;Moddemann et al, 2022;Twigg et al, 2013;Yamada et al, 2021). A summary of the reported characteristics of patients with ERF variants is presented in Table 1.…”

Section: Discussionmentioning

confidence: 99%

“…Yumi Enomoto and Takuya Naruto performed the bioinformatics experiments and contributed to the genetics experiments. Yasuhiro Hirano and Yukiko Kuroda recruited T A B L E 1 Summary of the clinical data for reported patients with pathogenic ERF variants (Chaudhry et al, 2015;Glass et al, 2019;Körberg et al, 2020;Moddemann et al, 2022;Twigg et al, 2013;Yamada et al, 2021).…”

Section: Author Contributionsmentioning

confidence: 99%

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Noonan syndrome‐like phenotype associated with an ERF frameshift variant

Hirano,

Kuroda,

Enomoto

et al. 2024

American J of Med Genetics Pt A

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Noonan syndrome is a so‐called “RASopathy,” that is characterized by short stature, distinctive facial features, congenital heart defects, and developmental delay. Of individuals with a clinical diagnosis of Noonan syndrome, 80%–90% have pathogenic variants in the known genes implicated in the disorder, but the molecular mechanism is unknown in the remaining cases. Heterozygous pathogenic variants of ETS2 repressor factor (ERF), which functions as a repressor in the RAS/MAPK signaling pathway, cause syndromic craniosynostosis. Here, we report an ERF frameshift variant cosegregating with a Noonan syndrome‐like phenotype in a family. The proband was a 3‐year‐old female who presented with dysmorphic facial features, including proptosis, hypertelorism, slightly down slanted palpebral fissures, low‐set posteriorly rotated ears, depressed nasal bridge, short stature, and developmental delay. Exome sequencing of the proband identified a heterozygous ERF variant [NM_006494.4: c.185del p.(Glu62Glyfs*15)]. Her mother and sister showed a similar phenotype and had the same heterozygous ERF variant. A large proportion of the previously reported patients with syndromic craniosynostosis and pathogenic ERF variants also showed characteristic features that overlap with those of Noonan syndrome. The present finding supports an association between heterozygous ERF variants and a Noonan syndrome‐like phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Author Contributionsmentioning

confidence: 99%

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Noonan syndrome‐like phenotype associated with an ERF frameshift variant

Hirano,

Kuroda,

Enomoto

et al. 2024

American J of Med Genetics Pt A

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“…7,8,9 A recent case report described a child with a diagnosis of Noonan syndrome who was found to harbour a heterozygous ERF truncating variant. 10 Since the ‘Rasopathies’ are known to be associated with variable presentations of physiological and psychosocial developmental disorders 11,7,8 and given the involvement of ERF in RAS signal transduction, we hypothesised that reduced expression of ERF could be associated with similar features.…”

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confidence: 99%

Cognitive, Behavioural, Speech, Language and Developmental Outcomes Associated with Pathogenic Variants in the ERF Gene

Care

Luscombe

Wall

et al. 2022

Journal of Craniofacial Surgery

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: Pathogenic variants of the ERF gene were previously associated with craniosynostosis, craniofacial dysmorphism and Chiari malformation. This study investigates cognitive, behavioural, speech, language, and developmental outcomes in the first 5 children identified at the Oxford Craniofacial Unit as having ERF-related craniosynostosis, together with three of their carrier parents. There were no consistent findings related to overall intelligence. However, a pattern of cognitive difficulties is described, which includes poor attention, impulsivity and difficulties with functional fine motor skills, such as handwriting. A high frequency of speech, language and communication difficulties was evident, which was most often related to early language difficulties, speech sound difficulties, hyponasal resonance and concern regarding social communication skills and emotional immaturity. It was common for these children to have needed input from ear, nose and throat services. Problems with tonsils and/or adenoids and/ or fluctuating conductive hearing loss were found which may be contributors to early speech, language and communication difficulties. The authors make recommendations regarding the need for formal assessment of a range of developmental aspects upon diagnosis of a pathogenic variant in the ERF gene. The aim of this report is to give clinical guidance to anyone who may have care of patients with the ERF-related mutation.

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