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Objective: To define sonographic criteria that may improve the prenatal diagnosis of Noonan syndrome by targeted DNA testing., Methods: We searched our Fetal Medicine Unit records for all cases with a final diagnosis of Noonan syndrome. A literature review was undertaken to identify the sonographic features of Noonan syndrome fetuses. Information was pooled to define the most common features., Results: In our database, we identified three cases of Noonan syndrome. The diagnosis was suspected prenatally in two of them. Thirty-nine cases were identified in the literature. In the presented cases we show that suspicion of Noonan syndrome should arise when, after an increased nuchal translucency, ultrasound investigation in the second trimester shows a persistant nuchal fold (NF) or cystic hygroma in combination with at least one of the following features: hydrops fetalis, pleural effusion, cardiac anomalies, polyhydramnios or specific facial abnormalities., Conclusion: Prenatal ultrasound findings in Noonan syndrome can be subtle and aspecific, but when specific characteristics are present additional targeted DNA analysis is indicated., (Copyright © 2011 John Wiley & Sons, Ltd.)

Study Question: Do bi-allelic variants in the genes encoding the MSH4/MSH5 heterodimer cause male infertility?Summary Answer: We detected biallelic, (likely) pathogenic variants in MSH5 (4 men) and MSH4 (3 men) in six azoospermic men, demonstrating that genetic variants in these genes are a relevant cause of male infertility.What Is Known Already: MSH4 and MSH5 form a heterodimer, which is required for prophase of meiosis I. One variant in MSH5 and two variants in MSH4 have been described as causal for premature ovarian insufficiency (POI) in a total of five women, resulting in infertility. Recently, pathogenic variants in MSH4 have been reported in infertile men. So far, no pathogenic variants in MSH5 had been described in males.Study Design, Size, Duration: We utilized exome data from 1305 men included in the Male Reproductive Genomics (MERGE) study, including 90 males with meiotic arrest (MeiA). Independently, exome sequencing was performed in a man with MeiA from a large consanguineous family.Participants/materials, Setting, Methods: Assuming an autosomal-recessive mode of inheritance, we screened the exome data for rare, biallelic coding variants in MSH4 and MSH5. If possible, segregation analysis in the patients' families was performed. The functional consequences of identified loss-of-function (LoF) variants in MSH5 were studied using heterologous expression of the MSH5 protein in HEK293T cells. The point of arrest during meiosis was determined by γH2AX staining.Main Results and the Role Of Chance: We report for the first time (likely) pathogenic, homozygous variants in MSH5 causing infertility in 2 out of 90 men with MeiA and overall in 4 out of 902 azoospermic men. Additionally, we detected biallelic variants in MSH4 in two men with MeiA and in the sister of one proband with POI. γH2AX staining revealed an arrest in early prophase of meiosis I in individuals with pathogenic MSH4 or MSH5 variants. Heterologous in vitro expression of the detected LoF variants in MSH5 showed that the variant p.(Ala620GlnTer9) resulted in MSH5 protein truncation and the variant p.(Ser26GlnfsTer42) resulted in a complete loss of MSH5.Large Scale Data: All variants have been submitted to ClinVar (SCV001468891-SCV001468896 and SCV001591030) and can also be accessed in the Male Fertility Gene Atlas (MFGA).Limitations, Reasons For Caution: By selecting for variants in MSH4 and MSH5, we were able to determine the cause of infertility in six men and one woman, leaving most of the examined individuals without a causal diagnosis.Wider Implications Of the Findings: Our findings have diagnostic value by increasing the number of genes associated with non-obstructive azoospermia with high clinical validity. The analysis of such genes has prognostic consequences for assessing whether men with azoospermia would benefit from a testicular biopsy. We also provide further evidence that MeiA in men and POI in women share the same genetic causes.Study Funding/competing Interest(s): This study was carried out within the frame of the German Research Foundation sponsored Clinical Research Unit 'Male Germ Cells: from Genes to Function' (DFG, CRU326), and supported by institutional funding of the Research Institute Amsterdam Reproduction and Development and funds from the LucaBella Foundation. The authors declare no conflict of interest. [ABSTRACT FROM AUTHOR]