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.

中文翻译：

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与双等位基因 LZTR1 变异相关的常染色体隐性努南综合征。


目的 描述常染色体隐性遗传努南综合征的分子遗传学特征。方法 家庭对儿童及其父母的努南综合征特征进行表型分析。两个多重家族进行了连锁分析。外显子组、基因组或多基因组测序用于鉴定变异。通过逆转录聚合酶链反应评估观察到的剪接变体的分子后果。结果 对 12 个家庭共 23 名具有努南综合征特征的受影响儿童进行了评估。表型范围包括轻度受影响的患者，但对一些患有心脏病和白血病的患者来说是致命的。所有的父母都没有受到影响。使用隐性模型的连锁分析支持染色体 22q11 中的一个候选区域，其中包括 LZTR1，之前显示该区域在以显性模式遗传的努南综合征患者中存在突变。对 21 名活产患者和一名死产患者的测序分析发现了 LZTR1 中的双等位基因致病性变异，包括假定的功能丧失、错义以及受影响儿童的规范和非规范剪接变异，其父母是杂合的、临床上未受影响的父母以及杂合或正常基因型在未受影响的兄弟姐妹中。结论 这些临床和遗传数据证实了一种常染色体隐性遗传的努南综合征的存在，并确定了 LZTR1 的双等位基因突变。