Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Genet Med 2018 10 22;20(10):1175-1185. Epub 2018 Feb 22.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose: To characterize the molecular genetics of autosomal recessive Noonan syndrome.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2017.249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105555PMC
October 2018
167 Reads

Publication Analysis

Top Keywords

noonan syndrome
20
autosomal recessive
12
syndrome inherited
8
linkage analysis
8
features noonan
8
families underwent
8
recessive noonan
8
noonan
6
variants
5
syndrome
5
disease leukemia
4
lethal cardiac
4
leukemia parents
4
cardiac disease
4
parents heterozygous
4
analysis recessive
4
clinically unaffected
4
model supported
4
recessive model
4
unaffected parents
4

Similar Publications