RESUMEN
Constitutional heterozygous mutations in CHEK2 gene have been associated with hereditary cancer risk. To date, only a few homozygous CHEK2 mutations have been reported in families with cancer susceptibility. Here, we report two unrelated individuals with a personal and familial cancer history in whom biallelic CHEK2 alterations were identified. The first case resulted homozygous for the CHEK2 c.793-1 G > A (p.Asp265Thrfs*10) variant, and the second one was found to be compound heterozygous for the c.1100delC (p.Thr367Metfs*15) and the c.1312 G > T (p.Asp438Tyr) variants. Multiple cytogenetic anomalies were demonstrated on peripheral lymphocytes of both patients. A literature revision showed that a single other CHEK2 homozygous variant was previously associated to a constitutional randomly occurring multi-translocation karyotype from peripheral blood in humans. We hypothesize that, at least some biallelic CHEK2 mutations might be associated with a novel disorder, further expanding the group of chromosome instability syndromes. Additional studies on larger cohorts are needed to confirm if chromosomal instability could represent a marker for CHEK2 constitutionally mutated recessive genotypes, and to investigate the cancer risk and the occurrence of other anomalies typically observed in chromosome instability syndromes.
Asunto(s)
Neoplasias de la Mama , Proteínas Serina-Treonina Quinasas , Humanos , Femenino , Proteínas Serina-Treonina Quinasas/genética , Predisposición Genética a la Enfermedad , Quinasa de Punto de Control 2/genética , Mutación , Genotipo , Inestabilidad CromosómicaAsunto(s)
Ácidos Nucleicos Libres de Células , Leucemia Linfocítica Crónica de Células B , Adulto , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Embarazo , Mujeres Embarazadas , Diagnóstico Prenatal , Trisomía/diagnóstico , Trisomía/genética , Síndrome de la Trisomía 13 , Síndrome de la Trisomía 18RESUMEN
X-linked intellectual disability accounts for 10-12% of cases of cognitive impairment in males. Mutations in IL1RAPL1 are an emerging form of apparently non-syndromic X-linked intellectual disability. We report a 8-year-old intellectually disabled boy with speech delay, and unusual facial and digital anomalies who showed a novel and complex IL1RAPL1 rearrangement. It was defined by two intragenic non-contiguous duplications inherited from the unaffected mother. Chromosome X inactivation study on the mother's blood leukocytes, urinary sediment and buccal swab did not show a significant skewed inactivation. Comparison with previously described patients with IL1RAPL1 disruption was carried. Although data on craniofacial features were scanty in many papers, subtle facial dysmorphism with a thin upper lip seemed a quietly represented picture without any other genotype-phenotype correlations. Our study expands the molecular repertoire of IL1RAPL1 mutations in intellectual disability and points out the need of more accurate clinical descriptions to better define the related phenotype.
