Inspired by a colleague's patient. A 16 year old adolescent male with a history of intrauterine growth retardation and subsequent postnatal growth retardation, feeding difficulties after birth, progressive hearing loss, annular pancreas, hyperopia with anomalous optic nerves and thick corneas, pericardial effusion requiring pericardiectomy, multiple vertebral anomalies, widened central spinal canal, growth hormone resistance, submucous cleft palate, syndactyly of hands and feet, peg like teeth, immunodeficiency requiring IVIG therapy, Legg-Calve-Perthes disease of the right hip, and multiple dysplastic moles of his skin. He also has learning disability and developmental delay.
He has had 22 surgeries including G tube for feedings. He has cochlear implants for progressive hearing loss. He has right hip and leg pain after spinal surgery.
Whole exome sequencing demonstrated a heterozygous, likely deleterious mutation c.196A>G(p.R66G) in the CDC42 gene.
Takenouchi T, Kosaki R, Niizuma T, Hata K, Kosaki K. Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay. Am J Med Genet A. 2015 Nov;167A(11):2822-5.
The combinatory phenotype of thrombocytopenia and developmental delay has been described for two genetic conditions: a chromosome 11q deletion that is referred to as Jacobsen syndrome, and a 21q22 microdeletion syndrome. Herein, we report a young girl who presented with persistent macrothrombocytopenia and a developmental delay. Whole exome sequencing revealed a de novo amino acid substitution in CDC42, a critical regulator of the cytoskeleton. Our observation recapitulates observations in mice lacking Cdc42. We suggest that this CDC42 mutation may represent yet another mechanism leading to the combinatory phenotype of persistent macrothrombocytopenia and developmental delay.
Takenouchi T, Okamoto N, Ida S, Uehara T, Kosaki K. Further evidence of a
mutation in CDC42 as a cause of a recognizable syndromic form of
thrombocytopenia. Am J Med Genet A. 2016 Apr;170A(4):852-5.
We previously documented a girl with macrothrombocytopenia and developmental delay who carried a de novo mutation in CDC42, which plays pivotal roles in the cell cycle and the formation of the actin cytoskeleton. The phenotype of mice lacking Cdc42 was strikingly similar to that of the reported patient, indicating that the mutation in CDC42 causes a new syndromic form of thrombocytopenia. We, herein, report another unrelated female patient with a similar phenotype and a de novo mutation in the same CDC42. The present observation provides further evidence supporting the notion that a mutation in CDC42 causes a recognizable syndromic form of thrombocytopenia. The cardinal features of this entity include macrothrombocytopenia, developmental delay, lymphedema in the lower extremities, camptodactyly, and distinctive facial features.
Hori K, Nagai T, Shan W, Sakamoto A, Abe M, Yamazaki M, Sakimura K, Yamada K,
Hoshino M. Heterozygous Disruption of Autism susceptibility candidate 2 Causes
Impaired Emotional Control and Cognitive Memory. PLoS One. 2015 Dec
Mutations in the Autism susceptibility candidate 2 gene (AUTS2) have been associated with a broad range of psychiatric illnesses including autism spectrum disorders, intellectual disability and schizophrenia. We previously demonstrated that the cytoplasmic AUTS2 acts as an upstream factor for the Rho family small GTPase Rac1 and Cdc42 that regulate the cytoskeletal rearrangements in neural cells. Moreover, genetic ablation of the Auts2 gene in mice has resulted in defects in neuronal migration and neuritogenesis in the developing cerebral cortex caused by inactivation of Rac1-signaling pathway, suggesting that AUTS2 is required for neural development. In this study, we conducted a battery of behavioral analyses on Auts2 heterozygous mutant mice to examine the involvement of Auts2 in adult cognitive brain functions. Auts2-deficient mice displayed a decrease in exploratory behavior as well as lower anxiety-like behaviors in the absence of any motor dysfunction. Furthermore, the capability for novel object recognition and cued associative memory were impaired in Auts2 mutant mice. Social behavior and sensory motor gating functions were, however, normal in the mutant mice as assessed by the three-chamber test and prepulse inhibition test, respectively. Together, our findings indicate that AUTS2 is critical for the acquisition of neurocognitive function.