{
  "abstract": "Introduction SPECC1L encodes a cytoskeletal-associated protein essential for neural crest cell migration and tissue morphogenesis. SPECC1L pathogenic variants are implicated in variably expressive disorders such as Teebi Hypertelorism Syndrome 1 (TBHS1) and oblique facial clefting. Most TBHS1-associated pathogenic variants cluster in the CCD2 and CHD domains, disrupting interactions with actin filaments and microtubules. Here, we report a novel pathogenic mechanism involving an intragenic deletion that disrupts SPECC1L N-terminal intrinsically disordered region (IDR), sparing the functional domains.Methods An in vitro overexpression assay in HEK293 cells used to assess SPECC1L expression and the deletion functional impact. A literature review was conducted to delineate the variability in SPECC1L-related phenotypes.Results The proband and father had craniofacial dysmorphisms consistent with TBHS1 without congenital anomalies or neurodevelopmental delay. WGS identified a novel heterozygous intragenic SPECC1L exon 3 deletion, encompassing the canonical start codon. Functional assays confirmed translation from a downstream alternative start codon, resulting in stable production of truncated isoforms lacking part of the N-terminal IDR.Conclusion This is the first report of SPECC1L deletion affecting the canonical start codon and N-terminal IDR. The milder phenotype suggests that the N-terminal IDR may affect neural crest development, and its disruption may contribute to developmental defects.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical and Molecular Genetics, King’s College London, London UK",
        "Department of Clinical Genetics, Guy’s and St. Thomas’ NHS Trust, London, UK"
      ],
      "name": "Arwa Babai"
    },
    {
      "affiliations": [
        "Department of Medical and Molecular Genetics, King’s College London, London UK",
        "Department of Clinical Genetics, Guy’s and St. Thomas’ NHS Trust, London, UK",
        "Serviço de Genética Médica, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal"
      ],
      "name": "Daniela Oliveira"
    },
    {
      "affiliations": [
        "Department of Medical and Molecular Genetics, King’s College London, London UK"
      ],
      "name": "Andriana Gialeli"
    },
    {
      "affiliations": [
        "South East Genomics Laboratory Hub, Guy’s Hospital, London, UK"
      ],
      "name": "Malgorzata Drozniewska"
    },
    {
      "affiliations": [
        "Department of Medical and Molecular Genetics, King’s College London, London UK"
      ],
      "name": "Yaroslav Kainov"
    },
    {
      "affiliations": [
        "Department of Medical and Molecular Genetics, King’s College London, London UK",
        "Department of Clinical Genetics, Guy’s and St. Thomas’ NHS Trust, London, UK"
      ],
      "name": "Cristina Dias"
    }
  ],
  "title": "P21 Disruption of SPECC1L translation initiation by intragenic deletion: novel pathogenic mechanism in Teebi-Hypertelorism syndrome",
  "uid": "c3c5f009-addb-58e9-aa81-4012fd7a892f"
}