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International audience; We present the phenotypes of seven previously unreported patients with Marbach-Schaaf neurodevelopmental syndrome, all carrying the same recurrent heterozygous missense variant c.1003C>T (p.Arg335Trp) in PRKAR1B. Clinical features of this cohort include global developmental delay and reduced sensitivity to pain, as well as behavioral anomalies. Only one of the seven patients reported here was formally diagnosed with autism spectrum disorder (ASD), while ASD-like features were described in others, overall indicating a lower prevalence of ASD in Marbach-Schaaf neurodevelopmental syndrome than previously assumed. The clinical spectrum of the current cohort is similar to that reported in the initial publication, delineating a complex developmental disorder with behavioral and neurologic features. PRKAR1B encodes the regulatory subunit R1beta of the protein kinase A complex (PKA), and is expressed in the adult and embryonal central nervous system in humans. PKA is crucial to a plethora of cellular signaling pathways, and its composition of different regulatory and catalytic subunits is cell-type specific. We discuss potential molecular disease mechanisms underlying the patients' phenotypes with respect to the different known functions of PKA in neurons, and the phenotypes of existing R1beta-deficient animal models.

To examine the diagnostic yield of trio exome sequencing in fetuses with multiple structural defects with no pathogenic findings in cytogenetic and microarray analyses.We recruited 51 fetuses with two or more defects, non-immune fetal hydrops or fetal akinesia deformation syndrome|or fetal akinesia deformation sequence (FADS). Trio exome sequencing was performed on DNA from chorionic villi samples and parental blood. Detection of genomic variation and prioritization of clinically relevant variants was performed according to in-house standard operating procedures.Median maternal and gestational age was 32.0 years and 21.0 weeks, respectively. Forty-three (84.3%) fetuses had two or more affected organ systems. The remaining fetuses had isolated fetal hydrops or FADS. In total, the exome analysis established the genetic cause for the clinical abnormalities in 22 (43.1%, 95% CI 29.4%-57.8%) pregnancies.In fetuses with multiple defects, hydrops or FADS and normal standard genetic results, trio exome sequencing has the potential to identify genetic anomalies in more than 40% of cases.

Ayme-Gripp syndrome is a multisystemic disorder caused by a heterozygous variation in the MAF gene (OMIM*177075). Key features are congenital cataracts, sensorineural hearing loss, and a characteristic facial appearance. In a proportion of individuals, pericardial effusion or pericarditis has been reported as part of the phenotypic spectrum. In the present case, a large persistent cytokine-enriched pericardial effusion was the main pre- and postnatal symptom that led to the clinical and later molecular diagnosis of Ayme-Gripp syndrome. In the postnatal course, the typical Ayme-Gripp syndrome-associated features bilateral cataracts and hearing loss were diagnosed. We propose that activating dominant variants in the cytokine-modulating transcription factor c-MAF causes cytokine-enriched pericardial effusions possibly representing a key feature of Ayme-Gripp syndrome.

Holoprosencephaly (HPE) has been defined as a distinct clinical entity with characteristic facial gestalt, which may-or may not-be associated with the true brain malformation observed post-mortem in autopsy or in pre- or postnatal imaging. Affected families mainly show autosomal dominant inheritance with markedly reduced penetrance and extremely broad clinical variability even between mutation carriers within the same families. We here present advances in prenatal imaging over the last years, increasing the proportion of individuals with HPE identified prenatally including milder HPE forms and more frequently allowing to detect more severe forms already in early gestation. We report the results of diagnostic genetic testing of 344 unrelated patients for HPE at our lab in Germany since the year 2000, which currently with the application of next generation sequencing (NGS) panel sequencing identifies causal mutations for about 31% (12/38) of unrelated individuals with normal chromosomes when compared to about 15% (46/306) using conventional Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). More comprehensive genetic testing by our in house NGS panel sequencing of 10 HPE associated genes (MiSeq (TM) and NextSeq (TM) 500, Illumina, Inc., San Diego, CA) not only allowed to include genes with smaller contribution to the phenotype, but may also unravel additional low frequency or more common genetic variants potentially contributing to the observed large intrafamiliar variability and may ultimately guide our understanding of the individual clinical manifestation of this complex developmental disorder.

Cerebral cavernous malformations (CCM) are prevalent vascular malformations occurring in familial autosomal dominantly inherited or isolated forms. Once CCM are diagnosed by magnetic resonance imaging, the indication for genetic testing requires either a positive family history of cavernous lesions or clinical symptoms such as chronic headaches, epilepsy, neurological deficits, and hemorrhagic stroke or the occurrence of multiple lesions in an isolated case. Following these inclusion criteria, the mutation detection rates in a consecutive series of 105 probands were 87% for familial and 57% for isolated cases. Thirty-one novel mutations were identified with a slight shift towards proportionally more CCM3 mutations carriers than previously published (CCM1: 60%, CCM2: 18%, CCM3: 22%). In-frame deletions and exonic missense variants requiring functional analyses to establish their pathogenicity were rare: An in-frame deletion within the C-terminal FERM domain of CCM1 resulted in decreased protein expression and impaired binding to the transmembrane protein heart of glass (HEG1). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. Since fulminant disease courses during the first years of life were observed in CCM1 and CCM3 mutation carriers, predictive testing of minor siblings became an issue. peerReviewed

Interstitial deletions of the short arm of chromosome 3 are rare. We report on a 3-year-old girl with intellectual disability, muscular hypotonia, strabismus, and facial anomalies in whom an interstitial 1.24 Mb deletion in 3p25.3-p26.1 was detected by SNP array analysis. The deleted region harbors 11 RefSeq genes including CAV3 and SRGAP3/MEGAP, which had been associated with muscle disorders and intellectual disability, respectively. The deletion overlaps with a slightly larger deletion in a girl with a more complex phenotype including congenital heart defect and epilepsy, which indicates that haploinsufficiency of one or several of the genes in the deleted interval causes intellectual deficits, but not heart defects or epilepsy. Thus, the patient broadens our knowledge of the phenotypic consequences of deletions in 3p25.3-p26.1 and facilitates genotype-phenotype correlations for chromosome aberrations of this region.