Here we describe two unrelated patients, a 5 years old male and a 7 years old female referred as Smith-Magenis syndrome-like phenotype. Indeed, they are characterized by craniofacial dysmorphisms, intellectual disability, language impairment, behavioural problems, and sleep disturbance. As RAI1 mutational study was negative, high resolution array-CGH analysis was performed revealing in both patients a similar deletion at 6p25.1 yet unreported in Database of Genomic Variants. In detail, the male and female patients have respectively a 141 kb and a 304 kb microdeletion spanning 5’ of LYRM4 (encoding a protein required for nuclear and mitochondrial iron-sulfur protein biosynthesis) and 5’ of FARS2 (encoding a phenylalanyl-tRNA synthetase 2 precursor). Both rare CNVs are inherited by the healthy mothers. Consistent with a putative pathogenic role of the two probands CNVs, a similar deletion was reported in dizygotic twins with clinical features partially overlapping those of the patients herein described. Even twins CNV was inherited by their mother, who had however a borderline phenotype. Attempting to explain the lack of clinical signs in the mothers of our probands, we carried out RT-qPCR and Sanger sequencing on both genes. These analyses revealed the same expected transcript reduction in patients and mothers as compared to controls and no mutations in the coding regions. Thus, to unveil a second hit contributing to the patients’ phenotype, we sequenced the promoter regions of FARS2 and LYRM4 to search for variants dysregulating the unaffected alleles. The analysis did not evidence any variant that might concur to the patients’ phenotype. Up to now our cases are the second report on CNVs spanning the 5’ of FARS2 and LYRM4 genes. Overall two unrelated patients with the same genomic defect and an overlapping phenotype, according to a previous report, support a pathogenic role for the current 6p25.1 deletions. The identification of second hit is still elusive and further studies are needed to clarify the genotype-phenotype correlation.
Microdeletion in two unrelated patients with intellectual disability / M. Sciarrillo, A. Sironi, I. Bestetti, D. Milani, L. Larizza, P. Finelli. ((Intervento presentato al convegno Congresso Nazionale SIGU tenutosi a Torino nel 2016.
|Titolo:||Microdeletion in two unrelated patients with intellectual disability|
SCIARRILLO, MARIA (Primo)
SIRONI, ALESSANDRA (Secondo)
|Data di pubblicazione:||23-nov-2016|
|Parole Chiave:||6p25.1 microdeletion, LYRM4, FARS2|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
|Citazione:||Microdeletion in two unrelated patients with intellectual disability / M. Sciarrillo, A. Sironi, I. Bestetti, D. Milani, L. Larizza, P. Finelli. ((Intervento presentato al convegno Congresso Nazionale SIGU tenutosi a Torino nel 2016.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|