Atypical presentation of pediatric <i>BRAF</i> RASopathy with acute encephalopathy

Pezzani, Lidia; Marchetti, Daniela; Cereda, Anna; Caffi, Lorella; Manara, Ornella; Mamoli, Daniela; Pezzoli, Laura; Lincesso, Anna Rita; Perego, Loredana; Pellicioli, Isabella; Bonanomi, Ezio; Salvoni, Laura; Iascone, Maria

doi:10.1002/ajmg.a.40635

Cited by 28 publications

(46 citation statements)

References 20 publications

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“…Patients were both evaluated at our Immunology Outpatient clinic at 17 years of age (Table 1). Trio whole exome sequencing (trio‐WES) (Pezzani et al, 2018) performed in the family of P1 did not identify any significant variant in known syndromic primary immunodeficiencies (PID) genes (Bousfiha et al, 2020). A novel de novo heterozygous missense variant (NM_001429.3:c.4763T>C, p.(Met1588Thr)) in the exon 29 of EP300 was detected, which was not present in public databases or in our internal databases.…”

Section: Clinical Descriptions and Discussionmentioning

confidence: 99%

Identical EP300 variant leading to Rubinstein–Taybi syndrome with different clinical and immunologic phenotype

Saettini

Fazio

Bonati

et al. 2022

American J of Med Genetics Pt A

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The Rubinstein–Taybi syndrome (RSTS) is a rare developmental disorder characterized by craniofacial dysmorphisms, broad thumbs and toes, intellectual disability, growth deficiency, and recurrent infections. Mutations in the cyclic adenosine monophosphate response element‐binding protein (CREB)‐binding protein (CREBBP) or in the E1A‐associated protein p300 (EP300) genes have been demonstrated in 55% (RSTS1) and up to 8% of the patients (RSTS2), respectively. Dysfunction of immune response has been reported in a subgroup of individuals with RSTS. Here we characterize two patients carrying the same EP300 variant and distinctive RSTS features (including congenital heart abnormalities, short stature, feeding problems, and gastroesophageal reflux). Whole exome sequencing did not support a dual molecular diagnosis hypothesis. Nonetheless, patients showed distinct clinical manifestations and immunological features. The most severe phenotype was associated with reduced T‐cell production and diversity. This latter feature was confirmed in a control group of four RSTS patients.

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Section: Clinical Descriptions and Discussionmentioning

confidence: 99%

Identical EP300 variant leading to Rubinstein–Taybi syndrome with different clinical and immunologic phenotype

Saettini

Fazio

Bonati

et al. 2022

American J of Med Genetics Pt A

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“…Twenty-seven patients underwent targeted next-generation sequencing (NGS) with the use of different gene panels, including ANKRD11 : 26 patients were tested with a diagnostic targeted NGS panel, including the KBGS and CdLS-related genes, based on a custom Nextera Rapid Capture enrichment kit (Illumina, San Diego, CA, USA), and PT14 was tested with the TruSight One Sequencing Panel (Illumina), including 4813 genes. In PT23, the twin sister of PT22, a targeted PCR followed by Sanger sequencing was performed, while exome sequencing was performed on PT31 using the Agilent SureSelect Clinical Research Exome enrichment kit (Agilent, Santa Clara, CA, USA), as previously described [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

Expanding the Molecular Spectrum of ANKRD11 Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome

Bestetti

Crippa

Sironi

et al. 2022

IJMS

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KBG syndrome (KBGS) is a neurodevelopmental disorder caused by the Ankyrin Repeat Domain 11 (ANKRD11) haploinsufficiency. Here, we report the molecular investigations performed on a cohort of 33 individuals with KBGS clinical suspicion. By using a multi-testing genomic approach, including gene sequencing, Chromosome Microarray Analysis (CMA), and RT-qPCR gene expression assay, we searched for pathogenic alterations in ANKRD11. A molecular diagnosis was obtained in 22 out of 33 patients (67%). ANKRD11 sequencing disclosed pathogenic or likely pathogenic variants in 18 out of 33 patients. CMA identified one full and one terminal ANKRD11 pathogenic deletions, and one partial duplication and one intronic microdeletion, with both possibly being pathogenic. The pathogenic effect was established by RT-qPCR, which confirmed ANKRD11 haploinsufficiency only for the three deletions. Moreover, RT-qPCR applied to six molecularly unsolved KBGS patients identified gene downregulation in a clinically typical patient with previous negative tests, and further molecular investigations revealed a cryptic deletion involving the gene promoter. In conclusion, ANKRD11 pathogenic variants could also involve the regulatory regions of the gene. Moreover, the application of a multi-test approach along with the innovative use of RT-qPCR improved the diagnostic yield in KBGS suspected patients.

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“…Tests included array‐CGH and ES. Trio‐based ES was performed for the second fetus as described before 30 . Briefly, the exonic and flanking splice junction regions of the genome were captured using the Clinical Research Exome v.2 kit (Agilent Technologies, Santa Clara, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Trio-based ES was performed for the second fetus as described before. 30 Briefly, the exonic and flanking splice junction regions of the genome were captured using the Clinical Research Exome v.2 kit (Agilent Technologies, Santa Clara, CA). Sequencing was performed on a NextSeq500 Illumina system with 150 bp paired-end reads.…”

Section: Methodsmentioning

confidence: 99%

Family history is key to the interpretation of exome sequencing in the prenatal context: unexpected diagnosis of Basal Cell Nevus Syndrome

et al. 2022

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Objectives: To reach a molecular diagnosis for a family with two consecutive fetuses presenting with multiple congenital anomalies. Methods:The two fetuses underwent prenatal ultrasound, autopsy, radiologic, and genetic investigation. Genetic analysis included karyotype and array-CGH for both fetuses and trio-based whole exome sequencing (WES) only for the second fetus.Results: WES results, initially focusing on recessive or dominant de novo variants, were negative.However, as a result of new relevant information regarding family history, the variant c.648_651dup in the PTCH1 gene was identified as causative of the fetal phenotype. Conclusions:This case further highlights how WES data analysis and interpretation strongly rely on family history and robust genotype-phenotype correlation. This is even more relevant in the prenatal setting, where access to fetal phenotype is limited and prenatal recognition of many morbid genes is not fully explored. We also provide a detailed description of the prenatal manifestations of Basal Cell Nevus Syndrome. Key pointsWhat's already known about this topic? � The diagnosis of BCNS is usually reached postnatally and its prenatal manifestations are mostly known from familial cases What does this study add? � We provide a thorough picture of the prenatal presentation of BCNS in two fetuses � We underline how a comprehensive autoptic fetal examination may disclose diagnostic handles � We stress that the prenatal diagnosis of BCNS may be underestimated due to the current knowledge of this condition

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Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy

Cited by 28 publications

References 20 publications

Identical EP300 variant leading to Rubinstein–Taybi syndrome with different clinical and immunologic phenotype

Identical EP300 variant leading to Rubinstein–Taybi syndrome with different clinical and immunologic phenotype

Expanding the Molecular Spectrum of ANKRD11 Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome

Family history is key to the interpretation of exome sequencing in the prenatal context: unexpected diagnosis of Basal Cell Nevus Syndrome

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