Automated reanalysis, a novel way to diagnose an ultra-rare condition: Fibronectin-1-related spondylometaphyseal dysplasia (SMD-FN1). Issue 3 (July 2021)

• Record Type: Journal Article
• Authors: Sabir, Ataf H.; Singhal, Juhi; Man, Jessica; Mensah, Nana Ekuntan; Ahn, Joo Wook; Cheung, Moira S.; Irving, Melita
• Is Part Of: Clinical dysmorphology. Volume 30:Issue 3(2021)
• Publication Date: 2021-07
• Subjects: corner fractures -- Fibronectin-1 -- metaphyseal chondrodysplasia Brussels type -- panel app -- Russell-Silver syndrome -- short stature -- skeletal dysplasia -- SMD-FN1; Abnormalities, Human -- Periodicals; Genetic disorders -- Periodicals; Abnormalities -- periodicals; Abnormalities, Human; Periodicals; 616.042
• DOI: 10.1097/MCD.0000000000000369
• Languages: English
• ISSNs: 0962-8827

Abstract

Abstract : We report a further case of spondylometaphyseal dysplasia – corner fracture type due to the fibronectin-1 gene ( SMD-FN1 ) in a child originally thought to have metaphyseal chondrodysplasia-Brussels type (MCD Brussels). We highlight phenotypic differences with the SMD-FN1 published reports. This case is unique in terms of the method of molecular confirmation. Findings from the 100 000 Genomes Project were originally negative (in both tier 1 and 2); however, subsequent reanalysis, initiated by an automated search for new gene-disease associations in PanelApp, highlighted a candidate diagnostic variant. Our child had short stature, facial dysmorphism, spondylometaphyseal dysplasia and corner fractures and a heterozygous de novo missense variant in FN1 (c.675C>G p.(Cys225Trp), which was likely pathogenic. The variant matched the clinical and radiological features and a diagnosis of SMD-FN1 was confirmed. We explore the diagnostic journey of this patient, compare her findings with the previous 15 patients reported with SMD-FN1 and discuss the diagnostic utility of automated reanalysis. We consider differences and similarities between MCD Brussels and SMD-FN1, by reviewing literature on both conditions and assess whether they are in fact the same disorder.