Rare Causes and Differential Diagnosis in Patients With Silver-Russell Syndrome

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Braga, Barbara Leitao ; Scalco, Renata da Cunha ; Homma, Thais Kataoka ; Freire, Bruna Lucheze ; Cellin, Laurana De Polli ; Canton, Ana Pinheiro Machado ; Lerario, Antonio Marcondes ; Funari, Mariana Ferreira de Assis ; de Souza, Vinicius ; Bertola, Debora Romeo ; Malaquias, Alexsandra Christianne ; Mendonca, Berenice Bilharinho ; Jorge, Alexander Augusto de Lima

• Document type: Journal article
• Source: Clinical Genetics; v. N/A, p. 5-pg., 2024-11-25.

Abstract

Silver-Russell syndrome (SRS) is an imprinting disorder mainly characterized by pre- and postnatal growth restriction. Most SRS cases are due to 11p15.5 loss of methylation (11p15.5 LOM) or maternal uniparental disomy of chromosome 7 [UPD(7)mat], but several patients remain molecularly undiagnosed. This study describes the molecular investigation of children with a clinical diagnosis or suspicion of SRS at a tertiary center specialized in growth disorders. Thirty-nine patients were evaluated with multiplex ligation-dependent probe amplification, chromosomal microarray and/or massively parallel sequencing. The most common result was 11p15.5 LOM (n = 17; 43.5%), followed by UPD(7)mat (n = 2; 5.1%). Additionally, we found maternal duplications of the imprinting centers in 11p15.5 (n = 2; 5.1%), and genetic defects in SRS-causing genes (IGF2 and HMGA2) (n = 3; 7.7%; two mutations and one deletion). Alternative molecular diagnoses included UPD(14)mat (n = 1; 2,6%), UPD(20)mat (n = 1;2,6%), copy number variants (n = 2; 5.1%), and mutations in genes associated with other growth disorders (n = 4; 10.3%), leading to diagnoses of Temple syndrome, Mulchandani-Bhoj-Conlin syndrome, IGF-1 resistance (IGF1R), Bloom syndrome (BLM), Gabriele-De Vries syndrome (YY1), Intellectual developmental disorder autosomal dominant 50 with behavioral abnormalities (NAA15), and Intellectual developmental disorder 64 (ZNF292). These findings underscore the importance of establishing the molecular diagnosis of SRS and its differential diagnoses to guide appropriate management and genetic counseling. (AU)

• FAPESP's process: 22/10107-6 - Whole exome and genomic sequencing in the identification of new genes responsible for growth disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/10893-6 - Prospective evaluation of exome sequencing in the etiological investigation of syndromic short stature patients without clinical diagnosis
• Grantee: Bruna Lucheze Freire
• Support Opportunities: Scholarships in Brazil - Doctorate