Autosomal dominant Shwachman–Diamond syndrome with a novel heterozygous missense variant in the <i>SRP54</i> gene causing severe phenotypic features

McCarthy, Peter; Cotter, Maura B.; Smith, Owen

doi:10.1111/bjh.17853

Cited by 3 publications

(4 citation statements)

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“…Recently, SRP54 pathogenic variants have been associated with SCN and SDS‐like disease, with phenotypes including exocrine pancreatic insufficiency, neurodevelopmental delay, and skeletal dysplasia (Bellanne‐Chantelot et al, 2018; Carapito et al, 2017; Carden et al, 2018; Erdos et al, 2022; Goldberg et al, 2020; Manabe et al, 2022; McCarthy et al, 2022; Saettini et al, 2020; Tamura et al, 2021). SRP54 is a 54‐kDa signal recognition particle GTPase protein.…”

Section: Introductionmentioning

confidence: 99%

“…SBDS pathogenic variants are present in 75%-89% of SDS patients (Boocock et al, 2003;Kuijpers et al, 2005); however, new pathogenic variants in other genes are continually being discovered (Stepensky et al, 2017;Tummala et al, 2016). Recently, SRP54 pathogenic variants have been associated with SCN and SDS-like disease, with phenotypes including exocrine pancreatic insufficiency, neurodevelopmental delay, and skeletal dysplasia (Bellanne-Chantelot et al, 2018;Carapito et al, 2017;Carden et al, 2018;Erdos et al, 2022;Goldberg et al, 2020;Manabe et al, 2022;McCarthy et al, 2022;Saettini et al, 2020;Tamura et al, 2021). SRP54 is a 54-kDa signal recognition particle GTPase protein.…”

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confidence: 99%

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Severe congenital neutropenia, SRP54 pathogenicity, and a framework for surveillance

Fan

Vagher

Meznarich

et al. 2023

American J of Med Genetics Pt A

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Severe congenital neutropenia (SCN) is a rare disorder, often due to pathogenic variants in genes such as ELANE, HAX1, and SBDS. SRP54 pathogenic variants are associated with SCN and Shwachman‐Diamond‐like syndrome. Thirty‐eight patients with SRP54‐related SCN are reported in the literature. We present an infant with SCN, without classic Shwachman‐Diamond syndrome features, who presented with recurrent bacterial infections and an SRP54 (c.349_351del) pathogenic variant. Despite ongoing granulocyte colony‐stimulating factor therapy, this patient has no evidence of malignant transformation. Here we establish a framework for the future development of universal guidelines to care for this patient population.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Severe congenital neutropenia, SRP54 pathogenicity, and a framework for surveillance

Fan

Vagher

Meznarich

et al. 2023

American J of Med Genetics Pt A

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“…Biallelic pathogenic variants in the SBDS gene are found in >90% of SDS patients [ 6 ]. Recently, pathogenic variants in DNAJC21 (AR), EFL1 (AR), and SRP54 (AD) have been reported in SDS or SDS-like phenotypes in a few cases [ 7 , 8 , 9 , 10 , 11 , 12 ]. However, despite the fact that SBDS and EFL1 mutations have been associated with SDS1 (OMIM #260400) and SDS2 (OMIM#617941), respectively, only SRP54 has been associated with SDS-like conditions (OMIM#618752).…”

Section: Introductionmentioning

confidence: 99%

Phenotypic Variation in Two Siblings Affected with Shwachman-Diamond Syndrome: The Use of Expert Variant Interpreter (eVai) Suggests Clinical Relevance of a Variant in the KMT2A Gene

Taha

Paoli²,

Foroni

et al. 2022

Genes

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Introduction. Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive disorder characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and an increased risk for leukemic transformation. Biallelic mutations in the SBDS gene have been found in about 90% of patients. The clinical spectrum of SDS in patients is wide, and variability has been noticed between different patients, siblings, and even within the same patient over time. Herein, we present two SDS siblings (UPN42 and UPN43) carrying the same SBDS mutations and showing relevant differences in their phenotypic presentation. Study aim. We attempted to understand whether other germline variants, in addition to SBDS, could explain some of the clinical variability noticed between the siblings. Methods. Whole-exome sequencing (WES) was performed. Human Phenotype Ontology (HPO) terms were defined for each patient, and the WES data were analyzed using the eVai and DIVAs platforms. Results. In UPN43, we found and confirmed, using Sanger sequencing, a novel de novo variant (c.10663G>A, p.Gly3555Ser) in the KMT2A gene that is associated with autosomal-dominant Wiedemann–Steiner Syndrome. The variant is classified as pathogenic according to different in silico prediction tools. Interestingly, it was found to be related to some of the HPO terms that describe UPN43. Conclusions. We postulate that the KMT2A variant found in UPN43 has a concomitant and co-occurring clinical effect, in addition to SBDS mutation. This dual molecular effect, supported by in silico prediction, could help to understand some of the clinical variations found among the siblings. In the future, these new data are likely to be useful for personalized medicine and therapy for selected cases.

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“…[12,13] Recently, SRP54 PV have been associated with SCN and SDS-like disease, with phenotypes including exocrine pancreatic insufficiency, neurodevelopmental delay, and skeletal dysplasia. [14][15][16][17][18][19][20][21][22] SRP54 is a 54-kDa signal recognition particle GTPase protein. SRP54 PVs are associated with increased protein flexibility, impaired GTP binding, and complex formation with the SRP receptor.…”

Section: Introductionmentioning

confidence: 99%

Severe congenital neutropenia, SRP54 pathogenicity, and a Framework for Surveillance

Vagher

Meznarich

et al. 2022

Preprint

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Severe congenital neutropenia (SCN) is a rare disorder, often due to pathogenic variants (PV) in genes such as ELANE, HAX1, and SBDS.SRP54 PVs are associated with SCN and Shwachman-Diamond-like syndrome. Thirty-eight patients with SRP54-related SCN are reported in the literature. We present an infant with SCN, without classic Shwachman-Diamond syndrome features, who presented with recurrent bacterial infections and an SRP54 (c.349_351del) PV. Despite ongoing granulocyte colony-stimulating factor (G-CSF) therapy, there has been no evidence of malignant transformation. Here we establish a framework for future development of universal guidelines to care for this patient population.

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Autosomal dominant Shwachman–Diamond syndrome with a novel heterozygous missense variant in the SRP54 gene causing severe phenotypic features

Abstract: Establishment and validation of a standard protocol for the detection of minimal residual disease in B lineage childhood acute lymphoblastic leukemia by flow cytometry in a multi-center setting.

Cited by 3 publications

References 17 publications

Severe congenital neutropenia, SRP54 pathogenicity, and a framework for surveillance

Severe congenital neutropenia, SRP54 pathogenicity, and a framework for surveillance

Phenotypic Variation in Two Siblings Affected with Shwachman-Diamond Syndrome: The Use of Expert Variant Interpreter (eVai) Suggests Clinical Relevance of a Variant in the KMT2A Gene

Severe congenital neutropenia, SRP54 pathogenicity, and a Framework for Surveillance

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