Thrombin generation in two families with MYH9-related platelet disorder.

MYH9-related platelet disorders are inherited macrothrombocytopenias with additional clinical manifestations including renal failure, hearing loss, pre-senile cataract, and inclusion bodies in leucocytes that are present in different combinations. The MYH9 gene codes for the cytoplasmic contractile protein non-muscular myosin heavy chain IIA, present in several tissues. The bleeding tendency is usually mild to moderate but rarely, thrombotic complications are also seen. We report on the thrombin generation potential (ETP) in patients with MYH9-related disease with and without arterial thrombosis. In family A, four affected members [c.5521G>A mutation causing p.(Glu1841Lys)] were evaluated. Three of them had a moderate bleeding tendency and in two renal insufficiency and hearing loss were already present. These two patients had an arterial thrombosis (myocardial infarction and pons infarction, respectively) before 50 years of age. In family B, two members were affected [c.4679T>G, resulting in p.(Val1560Gly)]. Their bleeding tendency was mild (bleeding scores 4 and 3, respectively). Thrombelastography (ROTEM) was normal in all six individuals. ETP was below the normal range in family B. However, in family A, the two members affected by thrombosis had a normal ETP, indicating that other factors compensated for the low platelet count and might have contributed to the arterial thrombosis

Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum

CASK is a multi-domain scaffolding protein that interacts with the transcription factor TBR1 and regulates expression of genes involved in cortical development such as RELN. Here we describe a previously unreported X-linked brain malformation syndrome caused by mutations of CASK. All five affected individuals with CASK mutations had congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia, and severe mental retardation

High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors.

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.peerReviewe

Disruption of Neurexin 1 Associated with Autism Spectrum Disorder

Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of α-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs ∼750 kb 5′ to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the α-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD