This report describes developmental delay, dysmorphic facies, and brain anomalies, an autosomal dominant intellectual developmental disorder that has been associated with de novo missense mutations. The human gene implicated is U2AF2, which encodes U2 small nuclear RNA auxiliary factor 2, a component of the U2 auxiliary factor (U2AF), which is involved in pre-mRNA splicing. There is one high-scoring fly ortholog, Dmel\U2af50, for which multiple genetic reagents, including classical alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis, have been generated; and one moderate-scoring fly ortholog, Dmel\LS2.
Multiple UAS constructs of the human gene Hsap\U2AF2, including wild-type U2AF2 and genes carrying mutational lesions, have been introduced into flies. See the 'Disease-Implicated Variants' table below. Heterologous rescue (functional complementation) has been demonstrated for the lethal phenotype of neural-specific knockdown of Dmel\U2af50.
Pan-neuronal RNAi-mediated knockdown of Dmel\U2af50 is lethal at late pupal stages; the few survivors die shortly after eclosion. Pan-neuronal knockdown of Dmel\U2af50 results in a modest decrease in larval brain area, with severe structural defects of the larval mushroom body. Mushroom body-specific knockdownof Dmel\U2af50 is not lethal, and results in mild morphological deficits of larval mushroom bodies. Affected female adults exhibit changes in social space behavior, clustering closer to neighboring flies than do wild-type flies, which disperse throughout available space. Motor neuron-specific knockdown of Dmel\U2af50 results an enhancement of heat-induced motor paralysis. These phenotypes can be rescued by expression of wild-type Hsap\U2AF2, but are only partially rescued by variant isoforms, suggesting that the variants are partial loss-of-function alleles.
[updated Jan. 2024 by FlyBase; FBrf0222196]
[DEVELOPMENTAL DELAY, DYSMORPHIC FACIES, AND BRAIN ANOMALIES; DEVDFB](https://omim.org/entry/620535)
[U2 SMALL NUCLEAR RNA AUXILIARY FACTOR 2; U2AF2](https://omim.org/entry/191318)
A cohort of over 40 unrelated individuals exhibit a neurodevelopmental phenotype associated with U2AF2 de novo missense variants, with core features of global developmental, speech, and motor delays, mild-to-severe ID, hypotonia, seizures, frequent brain malformations, autistic features, behavioral disturbances, and a shared facial gestalt (Li, et al., 2024 pubmed:37962958; FBrf0258439).
Developmental delay, dysmorphic facies, and brain anomalies (DEVDFB) is characterized by global developmental delay with impaired intellectual development, speech delay, nonspecific dysmorphic facial features, hypotonia, and impaired overall growth with small head circumference. Most affected individuals have early-onset seizures that are variable in severity. Brain imaging typically shows hypoplasia of the corpus callosum and/or delayed myelination (Hiraide et al., 2021, pubmed:34112922; Kuroda et al., 2023, pubmed:37134193). [from MIM:614008; 2024.01.23]
Newly identified mutations in U2AF2 are de novo missense variants, and are clustered in the U2AF2 protein's two RRM recognition motifs (Li, et al., 2024 pubmed:37962958; FBrf0258439).
Developmental delay, dysmorphic facies, and brain anomalies (DEVDFB) is caused by heterozygous mutation in the U2AF2 gene on chromosome 19q13. [from MIM:620535; 2024.01.22]
U2AF2 is an essential pre-mRNA splicing factor that guides the early stages of splice-site choice by recognizing polypyrimidine tract consensus sequences near the 3-prime splice site (Sickmier et al., 2006, pubmed:16818232). [from MIM:191318; 2024.01.23]
High-scoring ortholog of human U2AF2.
