Unusual features in a child with Marshall-Smith syndrome due to a novel NFIX variant: Evidence for an abnormal protein function

• Published in: Gene reports 2021-03, Vol.22, p.100991, Article 100991
• Main Authors: Deconte, Desirée, dos Santos, Catarine Benta Lopes, de Morais, Camila Ohomoto, Yonamine, Tatiane Mayumi, Nogueira, Letícia Thaís, Ferreira, Maria Angélica Tosi, Franceschi, Vinícius Bonetti, Longhi, André Luís Soares, Villacis, Rolando André Rios, Rogatto, Silvia Regina, Ligabue-Braun, Rodrigo, Zen, Paulo Ricardo Gazzola, Rosa, Rafael Fabiano Machado, Fiegenbaum, Marilu
• Format: Article
• Language: English
• Subjects: Congenital glaucoma; Ectopic kidney; Marshall-Smith syndrome; NFIX gene; Trigonocephaly
• ISSN: 2452-0144; 2452-0144
• DOI: 10.1016/j.genrep.2020.100991

Marshall-Smith syndrome (MSS) is a rare genetic condition characterized by different clinical features, such as accelerated skeletal maturation, growth retardation, neuropsychomotor delay, and characteristic facial abnormalities. This study describes a 2-year-old boy presenting longiline appearance, macrocephalus with trigonocephaly, prominent eyes with bluish sclera, middle face hypoplasia, micrognathia, dysplastic ears, hirsutism, narrow and asymmetrical thorax, hypoplastic scrotal sac, cryptorchidism, joint laxity, hypoplastic toenails, and large sacral dimple with prominent coccyx. Abdominal ultrasonography showed an enlarged left ectopic kidney and skull computed tomography revealed signs of early closure of the metopic suture. High-resolution GTG banding karyotype and high-density CytoScan HD array did not identify abnormalities associated to the patient clinical findings. NFIX sequencing revealed a de novo variant consisted of a seven nucleotides duplication in exon 8. We suggest that some clinical findings, as glaucoma, trigonocephaly and ectopic kidney are underestimated and should be considered within the clinical spectrum of the syndrome. In addition, the NFIX variant identified in our patient is unusual among patients with MSS and has not yet been described in the literature. We present some mechanisms that could be involved in the impairment of proper NFIX protein function. •Trigonocephaly, congenital glaucoma and ectopic kidney as features for the Marshall-Smith syndrome clinical spectrum•New de novo variant (NG_032925.2:g.90963_90969dupCCAGCAG) found in a patient with Marshall-Smith syndrome•Haploinsuffiency, nonsense-mediated mRNA decay (NMD) escape and dominant negative protein effect as possible explanations for MSS phenotype