Intellectual Disability and Overgrowth -- a Case Caused By Novel Mutation of Nfix gene Based on Whole-Exon Sequencing

Presentation Number: LB SUN 35
Date of Presentation: April 2nd, 2017

Wei LU*1, Bing-bing WU2, Ping Zhang2, Hui-jun WANG2, Lin Yang2, Wen-hao Zhou2 and Fei-hong Luo2
1Children’s Hospital of Fudan University, Shanghai, CHINA, 2Children’s Hospital of Fudan University, Shanghai, China

Abstract

Aims: Intellectual disability and overgrowth can be seen in some genetic disorders. Here we report a patient showing moderate Intellectual disability with overgrowth (height > 3SD) , who caused by a novel mutation of NFIXgene identified by whole-exon sequencing (WES).

Methods: Genomic DNA from the proband was extracted from peripheral blood leukocyte. Karyotype analysis was performed on metaphase cells. Array-based comparative genomic hybridization of DNA from the patient’s peripheral blood lymphocytes and WES were performed respectively.

Results: The proband, a 4yr2mon old girl, is the first child of healthy nonconsanguineous Chinese parents. She was born by uterine-incision delivery after 41 weeks of gestation. Her birth weight was 3.5 kg. She showed an distinctive face including prominent forehead, high anterior hairline, downslanting palpebral fissures, prominent chin and blue sclera. During further development, delay in language and motor skills as well as poor coordination were noted. She presents poor wound healing, bruising susceptibility, accelerated skeletal maturation (+2.5 years) and constipation. Her heigt was 122cm (> 3SD) and her fingers were long. Brain MRI performed less white matter. Karyotyping was 46, XX and array CGH analysis was normal. Then we performed WES for this patient and identified a novel frameshift mutation of NFIXgene.

Discuss and conclusion: Recently, there have been several reports of patients with Sotos-like features who carry de novo disruption of the NFIX gene by either deletions or sequence variants. Although the small number of cases reported to date hinders identification of genotype–phenotype correlations for NFIX, a strong correlation has been observed between the classes of variant that cause Malan syndrome and Marshall–Smith syndrome, with Marshall–Smith syndrome seen only with frameshift or splice site variants in exons 6–8. But for our patient,her de novo c.177_178insGCGGATGT frameshift variant was seen in exon 2. We still need more cases to understand genotype–phenotype correlations. The phenotype is characterised by mild-to-moderate overgrowth, macrocephaly with a prominent forehead and moderate developmental delay, all features of NSD1-positive Sotos syndrome. Overgrowth is often postnatal in onset and is typically less marked than in Sotos syndrome. NFIX analysis should be considered in patients presenting with overgrowth, macrocephaly and developmental delay including those in whom Sotos syndrome has been considered clinically but are negative for pathogenic NSD1 variants or chromosome microdeletion.

 

Nothing to Disclose: WL, BBW, PZ, HJW, LY, WHZ, FHL