Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Johnston Jennifer J, van der Smagt Jasper J, Rosenfeld Jill A, Pagnamenta Alistair T, Alswaid Abdulrahman, Baker Eva H, Blair Edward, Borck Guntram, Brinkmann Julia, Craigen William, Dung Vu Chi, Emrick Lisa, Everman David B, van Gassen Koen L, Gulsuner Suleyman, Harr Margaret H, Jain Mahim, Kuechler Alma, Leppig Kathleen A, McDonald-McGinn Donna M, Can Ngoc Thi Bich, Peleg Amir, Roeder Elizabeth R, Rogers R Curtis, Sagi-Dain Lena, Sapp Julie C, Schäffer Alejandro A, Schanze Denny, Stewart Helen, Taylor Jenny C, Verbeek Nienke E, Walkiewicz Magdalena A, Zackai Elaine H, Zweier Christiane, Members of the Undiagnosed Diseases Network, Zenker Martin, Lee Brendan, Biesecker Leslie G
Аннотация
METHODS: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.
RESULTS: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.
CONCLUSION: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.