RESUMEN
Constitutional SMARCB1 mutations at 22q11.23 have been found in â¼50% of familial and <10% of sporadic schwannomatosis cases. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in â¼80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1.
Asunto(s)
Cromosomas Humanos Par 22/genética , Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal/genética , Modelos Moleculares , Neurilemoma/genética , Conformación Proteica , Factores de Transcripción/genética , Secuencia de Bases , Proteínas Cromosómicas no Histona/genética , ADN Complementario/genética , Proteínas de Unión al ADN/genética , Componentes del Gen , Genes Dominantes/genética , Humanos , Pérdida de Heterocigocidad , Repeticiones de Microsatélite/genética , Datos de Secuencia Molecular , Neurofibromatosis 2/genética , Linaje , Proteína SMARCB1 , Análisis de Secuencia de ADN , Factores de Transcripción/químicaRESUMEN
Pericentric chromosome inversions are often associated with infertility, recurrent pregnancy loss, and an increased risk for offspring with congenital anomalies. We report on a chromosome 1 inversion between 1p36.21 and 1q42.13, one of the largest described familial pericentric inversions of chromosome 1. The inversion was ascertained following the birth of a female with multiple congenital anomalies due to a recombinant chromosome 1. The inversion was subsequently detected or inferred in 16 healthy individuals over five generations. Interestingly, with a ratio of 16 carriers to 6 noncarriers, there appears to be transmission distortion of the inverted chromosome 1 within the family. Although there is no reported difficulty conceiving in the family, the risk of miscarriage is higher than predicted at 34% (13/38). The recurrence risk of a recombinant chromosome also appears to be lower than expected based on the mode of ascertainment. This case contributes to the spectrum of clinical features of chromosome 1 recombinants and raises the question of whether or not there is a selective advantage of the inverted chromosome at meiosis, conception, or post-zygotically that has contributed to transmission distortion of the inverted chromosome.
