76From a GeneMatcher-enabled international collaboration, we identified ten individuals with 77 intellectual disability, speech delay, ataxia and facial dysmorphism and a mutation in EBF3, 78 encoding a transcription factor required for neuronal differentiation. Structural assessments, 79 transactivation assays, in situ fractionation, RNA-seq and ChIP-seq experiments collectively 80 show that the mutations are deleterious and impair EBF3 transcriptional regulation. These 81 findings demonstrate that EBF3-mediated dysregulation of gene expression has profound 82 effects on neuronal development in humans. 83 84 85 ⏐ 4Intellectual disability (ID) is a common phenotype with extreme clinical and genetic 86 heterogeneity. Widespread application of whole-genome and whole-exome sequencing 87 (WES) has tremendously increased the elucidation of the genetic causes of non-syndromic 88 and syndromic forms of ID 1,2 . WES together with the freely accessible tool GeneMatcher 89 (http://genematcher.org) which brings together clinicians and researchers with an interest in 90 the same gene, significantly aid in identifying new disease genes 3 . 91 We investigated a family with three healthy and two affected children, who both 92 presented with global developmental delay, febrile seizures, and gait instability with frequent 93 falls. WES was performed in both probands and one healthy sibling. We initially 94 hypothesized a Mendelian recessive trait; however, we did not identify any rare, potentially 95 pathogenic biallelic variants in the affected siblings (data not shown). WES data were 96 analyzed for heterozygous variants absent in dbSNP138, 1000 Genomes Project, Exome 97 Variant Server, and ExAC Browser, shared by both affected subjects and absent in the healthy 98 sibling. This analysis identified 16 variants (Supplementary Table 1). We used objective 99 metrics from ExAC to prioritize genes intolerant to functional variation (pLI ≥0.9 and high 100 values for Z score) ( Supplementary Table 1) 101 (http://biorxiv.org/content/early/2015/10/30/030338); five genes were identified with strong 102 selection against various classes of variants for segregation analysis in the family 103 (Supplementary Table 1). Four variants were inherited from a healthy parent and/or were 104 present in two healthy siblings (Supplementary Table 2). The missense variant c.625C>T 105[p.(Arg209Trp)] in EBF3 was confirmed in both affected siblings and was absent in the father 106 and all healthy siblings ( Supplementary Fig. 1a and Supplementary Table 2). In leukocyte-107 derived DNA from the mother, the Sanger sequence profile showed a very low signal for the 108 mutated base (thymine) superimposed on the wild-type sequence (cytosine) suggesting that 109 she had somatic mosaicism for the EBF3 variant (Supplementary Fig. 1a) 4 . By cloning the 110 mutation-bearing EBF3 amplicon followed by sequencing of colony PCR products, we 111 ⏐ 5 confirmed the mother to be a mosaic carrier (18% and 4% of leukocytes and buccal cells, 112 respectively, wer...
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