Title |
Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants
|
---|---|
Published in |
Genetics in Medicine, February 2018
|
DOI | 10.1038/gim.2017.249 |
Pubmed ID | |
Authors |
Jennifer J Johnston, Jasper J van der Smagt, Jill A Rosenfeld, Alistair T Pagnamenta, Abdulrahman Alswaid, Eva H Baker, Edward Blair, Guntram Borck, Julia Brinkmann, William Craigen, Vu Chi Dung, Lisa Emrick, David B Everman, Koen L van Gassen, Suleyman Gulsuner, Margaret H Harr, Mahim Jain, Alma Kuechler, Kathleen A Leppig, Donna M McDonald-McGinn, Ngoc Thi Bich Can, Amir Peleg, Elizabeth R Roeder, R Curtis Rogers, Lena Sagi-Dain, Julie C Sapp, Alejandro A Schäffer, Denny Schanze, Helen Stewart, Jenny C Taylor, Nienke E Verbeek, Magdalena A Walkiewicz, Elaine H Zackai, Christiane Zweier, Martin Zenker, Brendan Lee, Leslie G Biesecker |
Abstract |
PurposeTo characterize the molecular genetics of autosomal recessive Noonan syndrome.MethodsFamilies 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.ResultsTwelve 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.ConclusionThese 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.Genet Med advance online publication, 22 February 2018; doi:10.1038/gim.2017.249. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 11 | 28% |
United Kingdom | 4 | 10% |
Saudi Arabia | 2 | 5% |
Australia | 2 | 5% |
India | 2 | 5% |
Italy | 1 | 3% |
Lithuania | 1 | 3% |
Taiwan | 1 | 3% |
Mexico | 1 | 3% |
Other | 0 | 0% |
Unknown | 14 | 36% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 25 | 64% |
Scientists | 8 | 21% |
Science communicators (journalists, bloggers, editors) | 3 | 8% |
Practitioners (doctors, other healthcare professionals) | 3 | 8% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 120 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 16 | 13% |
Student > Ph. D. Student | 13 | 11% |
Student > Bachelor | 12 | 10% |
Student > Master | 11 | 9% |
Student > Postgraduate | 6 | 5% |
Other | 18 | 15% |
Unknown | 44 | 37% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 34 | 28% |
Medicine and Dentistry | 24 | 20% |
Agricultural and Biological Sciences | 8 | 7% |
Nursing and Health Professions | 3 | 3% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 2% |
Other | 7 | 6% |
Unknown | 42 | 35% |