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FB2026_01
,
released March 12, 2026
This report describes the newly characterized disease neurodevelopmental disorder with language delay and seizures (NEDLDS); NEDLDS exhibits autosomal recessive inheritance. The gene implicated in this disease is TIAM1, which encodes a guanyl-nucleotide exchange factor that activates RHO-like GTPases and connects extracellular signals to cytoskeletal activities. There is a single high-scoring ortholog in Drosophila, sif, for which multiple genetic reagents have been generated classical loss-of-function mutations, RNAi targeting constructs, overexpression constructs, and alleles caused by insertional mutagenesis. Dmel\sif is also orthologous to human TIAM2 and is less closely related to multiple other human genes.
UAS constructs of the human Hsap\TIAM1 gene, including wild-type and variants associated with this disease, have been introduced into flies. Partial heterologous rescue (functional complementation) of the sif semi-lethal phenotype is observed. However, neurological phenotypes of sif are not rescued and high levels of Hsap\TIAM1 appear to be toxic. Results using variant constructs have been compared to those using the wild-type human gene; the characterized variants exhibit varying levels of loss of function. See the 'Disease-Implicated Variants' table below.
Dmel\sif is expressed in the larval and adult central nervous systems and is mainly expressed in a subset of neurons, but not in glia. Loss of sif reduces the survival rate to adulthood; surviving adults exhibit climbing defects, are prone to severe seizures, and have a shorter lifespan.
[updated Jul. 2022 by FlyBase; FBrf0222196]
[NEURODEVELOPMENTAL DISORDER WITH LANGUAGE DELAY AND SEIZURES; NEDLDS](https://omim.org/entry/619908)
[T-CELL LYMPHOMA INVASION AND METASTASIS 1; TIAM1](https://omim.org/entry/600687)
Developmental delay, intellectual disability, speech delay, and seizures are observed (Lu et al., 2022; pubmed:35240055, FBrf0253130).
Neurodevelopmental disorder with language delay and seizures (NEDLDS) is an autosomal recessive disorder characterized by global developmental delay with mild to severely impaired intellectual development and speech delay with poor or absent language. Affected individuals develop early-onset seizures that are usually well-controlled with medication. Additional features may include axial hypotonia, peripheral hypertonia, hypothyroidism, and nonspecific dysmorphic features or brain imaging abnormalities (Lu et al., 2022; pubmed:35240055). [from MIM:619908; 2022.07.20]
Based on a small number of individual, this disease exhibits autosomal recessive inheritance (Lu et al., 2022; pubmed:35240055, FBrf0253130).
Neurodevelopmental disorder with language delay and seizures (NEDLDS) is caused by homozygous or compound heterozygous mutation in the TIAM1 gene. [from MIM:619908; 2022.07.20]
TIAM1 encodes a guanyl-nucleotide exchange factor (GEF) that activates RHO-like GTPases and connects extracellular signals to cytoskeletal activities. Activates RAC1, CDC42, and to a lesser extent RHOA and their downstream signaling to regulate processes like cell adhesion and cell migration. [Gene Cards, TIAM1; 2022.04.18]
Many to one: 2 human genes to 1 Drosophila gene; additional related genes in both species.
Moderate- to high-scoring ortholog of TIAM1 and TIAM2 (1 Drosophila to 2 human; additional related genes in both species).