Abstract
SETBP1 mutations are associated with the Schinzel-Giedion syndrome (SGS), characterized by profound neurodevelopmental delay, typical facial features, and multiple congenital malformations (OMIM 269150). Refractory epilepsy is a common feature of SGS. Loss of function mutations have been typically associated with a distinct and milder phenotype characterized by intellectual disability and expressive speech impairment. Here we report three variants of SETBP1, two novel de novo truncating mutations, identified by NGS analysis of an Intellectual Disability gene panel in 600 subjects with non-specific neurodevelopmental disorders, and one missense identified by a developmental epilepsy gene panel tested in 56 pediatric epileptic cases. The three individuals carrying the identified SETBP1 variants presented mild to severe developmental delay and lacked the cardinal features of classical SGS. One of these subjects, carrying the c.1765C>T (p.Arg589*) mutation, had mild Intellectual Disability with speech delay; the second one carrying the c.2199_2203del (p.Glu734Alafs19*) mutation had generalized epilepsy, responsive to treatment, and moderate Intellectual Disability; the third patient showed a severe cognitive defects and had a history of drug resistant epilepsy with West syndrome evolved into a Lennox-Gastaut syndrome. This latter subject carries the missense c.2572G>A (p.Glu858Lys) variant, which is absent from the control population, reported as de novo in a subject with ASD, and located close to the SETBP1 hot spot for SGS-associated mutations. Our findings contribute to further characterizing the associated phenotypes and suggest inclusion of SETBP1 in the list of prioritized genes for the genetic diagnosis of overlapping phenotypes ranging from non-specific neurodevelopmental disorders to “developmental and epileptic encephalopathy” (DEE).
Highlights
Genotype-phenotype correlations for SETBP1 gene are extremely complex and clinically relevant
Deletions or truncating mutations resulting in loss of function (LoF) of SETBP1 protein have been reported in only 16 individuals with a distinct phenotype, the Autosomal Dominant Mental Retardation type 29 (MRD29, OMIM∗ 616078), characterized by subtle dimorphisms, expressive speech impairment with intact receptive language abilities, decreased fine motor skills, and hyperactivity or autistic traits [7, 8]
The stop codon c.1765C>T (p.Arg589∗) and the frameshift c.2199_2203del; p.Glu734Alafs19∗, are novel SETBP1 variants predicted to result in a truncated protein and were found in two patients of the neurodevelopmental delay (NDD) cohort (Case 1 and 2)
Summary
Genotype-phenotype correlations for SETBP1 gene are extremely complex and clinically relevant. In order to estimate the contribution of SETBP1 in phenotypes differing from classic SGS, we included SETBP1 in two NGS-targeted gene panels for the diagnosis of individuals with non-specific neurodevelopmental disorders (NDDs) or developmental and epileptic encephalopathy (DEE). We report a detailed clinical description of two individuals found to carry novel de novo SETBP1 loss of function variants contributing to reinforce genotype-phenotype correlation for this condition. We discuss challenges in the interpretation of variants of uncertain significance (VUSs) in syndromic genes in individuals in whom an overt syndromic diagnosis was not evident This is the case of the SETBP1 germline variant p.Glu858Lys, reported as somatic in myeloid malignancies, which we identified in a girl with severe ID and drug resistant epilepsy and found to be de novo in her reportedly unaffected mother. Microsatellite loci were amplified by PCR using fluorescently labeled primers, and labeled products were analyzed by capillary electrophoresis using the ABI 3100 DNA Analyzer and the Gene Mapper software
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