De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay

Abstract

The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype.

Keywords: DIP2; DIP2C; developmental delay; intellectual disability; speech articulation; speech delay.

Figure 1.

Column graphs showing age at independent sitting, walking and first words in patients with DIP2C variants. Patients are represented by solid columns numbered 1–23 on the X axis with girls represented by pink columns and boys represented by blue columns. The Y axis is labeled in months. Fig. 1A. Ages of independent sitting in 23 patients with DIP2C variants. Fig. 1B. Ages of independent walking in 23 patients with DIP2C variants. Fig. 1C. Ages of first words in 23 patients with DIP2C variants.

Figure 2.

Photograph of patients with heterozygous DIP2C variants*. Figs. 2A and 2B. Frontal and profile views of a 7-year-10-month-old male (patient 17); pictures are bracketed together. Figs. 2C and 2D. Frontal and profile views of a 6-year-4-month-old male (patient 18); pictures are bracketed together Figs. 2E and 2F. Frontal view of a 6-month-old female (patient 8) and frontal view of the same child at 9 months of age. Figs. 2G and 2H. Frontal and profile views of a 2-year-old female, the same child as in Figs. 2E–F. Figs. 2I and 2J. Frontal and profile views of a 5-year-old female, the same child as in Figs. E–H. Figs. 2E to 2J are bracketed together. Figs. 2K and 2L. Frontal and profile views of a 15-year-old female (patient 4); pictures are bracketed together. Fig. 2M and 2N. Frontal and profile views of a 10-year-old female (patient 5); pictures are bracketed together. *Patient ages at the time of photographs may differ from age recorded in Supplementary Table 1.

Figure 3.

Circular figure showing relative frequencies of facial and digital anomalies associated with heterozygous variants in DIP2C.

Figure 4A.. Spatiotemporal bioinformatic analyses of DIP2C expression in the human brain across developmental stages.

DIP2C expression across pre- and postnatal stages shows higher expression in early stages of brain development. Fig. 4A. Boxplots of gene expression (reads per kilobase per million, RPKM) of the neocortex shows that DIP2C is highly expressed during early stages of development. Right. Boxplots of gene expression (RPKM) of various other regions in the brain pooled including the hippocampus, amygdala, the ventral forebrain, the cerebral cortex and the Mediodorsal nucleus of thalamus. Stages correspond to the following post-conception weeks (pcw): 8–9pcw, 10–12pcw, 13–15pcw, 16–18pcw, 19–24pcw, 25–38pcw, Birth to 5 months, 6–18 months, 19 months-5 years, 6–11 years, 12–19 years, 20–29 years, 30–39 years, 40–49 years. Fig. 4B. Spatiotemporal bioinformatic analyses of DIP2C expression across human brain regions for prenatal and postnatal time periods. Regions of the brain correspond to the following: A1C - Primary auditory cortex; AMY - Amygdala; CBC - Cerebellar cortex; DFC - Dorsolateral prefrontal cortex; HIP - Hippocampus; IPC - Posterior inferior parietal cortex; ITC - Inferior temporal cortex; M1C – Primary motor cortex; MD - Mediodorsal nucleus of the thalamus; MFC - Medial prefrontal cortex; OFC - Orbital prefrontal cortex; S1C - Primary somatosensory cortex; STC – Superior temporal gyrus; STR - Striatum; V1C - Occipital cortex; VFC - Ventrolateral Prefrontal Cortex.