Growth hormone deficiency in megalencephaly-capillary malformation syndrome: An association with activating mutations in PIK3CA.

Megalencephaly-capillary malformation syndrome (MCAP) is a brain overgrowth disorder characterized by cortical malformations (specifically polymicrogyria), vascular anomalies, and segmental overgrowth secondary to somatic activating mutations in the PI3K-AKT-MTOR pathway (PIK3CA). Cases of growth failure and hypoglycemia have been reported in patients with MCAP, raising the suspicion for unappreciated growth hormone (GH) deficiency. Here we report an observational multicenter study of children with MCAP and GH deficiency.

RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit-successes and challenges.

Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women's Hospital NICU.

Atypical cerebral palsy: genomics analysis enables precision medicine.

Purpose: The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP).

A case of splenomegaly in CBL syndrome.

Introduction: We present a child with unexplained splenomegaly to highlight this feature as a presenting sign of the RASopathy CBL syndrome and to draw attention to the power and utility of next generation genomic sequencing for providing rapid diagnosis and critical information to guide care in the pediatric clinical setting.

Clinical Report: A 7-year-old boy presented with unexplained splenomegaly, attention deficit hyperactivity disorder, mild learning difficulties, easy bruising, mild thrombocytopenia, and subtle dysmorphic features. Extensive haematological testing including a bone marrow biopsy showed mild megaloblastoid erythropoiesis and borderline fibrosis.

The importance of considering monogenic causes of autoimmunity: A somatic mutation in KRAS causing pediatric Rosai-Dorfman syndrome and systemic lupus erythematosus.

Objectives: Clinicians need to be aware of the growing list of defined monogenic etiologies of autoimmune diseases. This is particularly relevant when evaluating children, as these rare monogenic forms of autoimmunity tend to present very early in life.

Methods And Results: By harnessing the transformative power of next generation sequencing, we made the unifying diagnosis of RAS-associated autoimmune leukoproliferative disease (RALD), caused by the somatic gain-of-function p.

Successful clinical treatment and functional immunological normalization of human MALT1 deficiency following hematopoietic stem cell transplantation.

MALT1 mutations impair normal NF-κB activation and paracaspase activity to cause a novel combined immunodeficiency. The clinical and immunological phenotype of MALT1 deficiency can be successfully treated with hematopoietic stem cell transplantation following reduced intensity conditioning.

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients.

IRAK-4 deficiency as a cause for familial fatal invasive infection by Streptococcus pneumoniae.

In this Letter to the Editor we report the case of two siblings with fatal pneumococcal meningitis as the initial manifestation of IRAK-4 deficiency caused by previously undescribed mutations in IRAK4. The letter also highlights the importance of invasive pneumococcal infection as a critical 'red flag' warning of the potential for an underlying primary immunodeficiency and identifies some of the challenges in making the clinical diagnosis of IRAK-4 deficiency.

Weaver Syndrome-Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function In Vitro.

Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27).

Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.

Individuals affected by restrictive cardiomyopathy (RCM) often develop heart failure at young ages resulting in early heart transplantation. Familial forms are mainly caused by mutations in sarcomere proteins and demonstrate a common genetic etiology with other inherited cardiomyopathies. Using next-generation sequencing, we identified two novel missense variants (p.

The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency.

Next-generation DNA sequencing has accelerated the genetic characterization of many human primary immunodeficiency diseases (PIDs). These discoveries can be lifesaving for the affected patients and also provide a unique opportunity to study the effect of specific genes on human immune function. In the past 18 months, a number of independent groups have begun to define novel PIDs caused by defects in the caspase recruitment domain family, member 11 (CARD11)-B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1 [CBM]) signalosome complex.

Somatic mosaicism for the p.His1047Arg mutation in PIK3CA in a girl with mesenteric lipomatosis.

We describe a patient who presented with a localized growth of mature fat tissue, which was surgically removed. MRI imaging identified diffuse increase in visceral adipose tissue. Targeted deep sequencing of the resected tissue uncovered a p.

Epistatic interactions between modifier genes confer strain-specific redundancy for Tgfb1 in developmental angiogenesis.

Tgfbm1 (chromosome 5, P = 8 x 10(-5)) and Tgfbm3 (chromosome 12, P = 6 x 10(-11)) were identified as loci that modify developmental angiogenesis of Tgfb1 -/- mice. Congenic mice validated these loci and demonstrated epistatic interaction between them. The novel locus, Tgfbm3, encompasses approximately 22 genes, colocalizes with both tumor susceptibility and atherosclerosis susceptibility loci, and is enriched in genes regulating cell growth and morphogenesis.

Genetic modifiers interact with maternal determinants in vascular development of Tgfb1(-/-) mice.

The transforming growth factor beta signaling family is a key player in genetic and multifactorial diseases, including hereditary hemorrhagic telangiectasia (HHT), cancer, atherosclerosis and immunomodulation. HHT types 1 and 2 are caused by loss of function mutations in ENG and ACVRL1; polymorphisms in TBRI and TGFB1 are also associated with altered risks for cancer and cardiovascular diseases. There is therefore much interest in identifying factors that influence transforming growth factor beta1 (TGFbeta1) action in vivo.