Development and Function of Immune Cells in an Adolescent Patient With a Deficiency in the Interleukin-10 Receptor.

Objective: Monogenic defects in the interleukin-10 (IL-10) pathway are extremely rare and cause infantile-onset inflammatory bowel disease (IBD)-like pathology. Understanding how immune responses are dysregulated in monogenic IBD-like diseases can provide valuable insight in "classical" IBD pathogenesis. Here, we studied long-term immune cell development and function in an adolescent IL-10 receptor (IL10RA)-deficient patient who presented in infancy with severe colitis and fistulizing perianal disease and is currently treated with immune suppressants.

The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.

Two proα1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proα2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as "COL4A1 mutation-related disorders.

Next-generation sequencing-based genome diagnostics across clinical genetics centers: implementation choices and their effects.

Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants.

Screening of TGFBR1, TGFBR2, and FLNA in familial mitral valve prolapse.

So far only mutations in the filamin A gene (FLNA) have been identified as causing familial mitral valve prolapse (MVP). Previous studies have linked dysregulation of the transforming growth factor beta (TGF-β) cytokine family to MVP. We investigated whether mutations in the TGF-β receptors genes type I (TGFBR1) and II (TGFBR2) underlie isolated familial MVP cases.

Novel no-stop FLNA mutation causes multi-organ involvement in males.

Mutations in FLNA (Filamin A, OMIM 300017) cause X-linked periventricular nodular heterotopia (XL-PNH). XL-PNH-associated mutations are considered lethal in hemizygous males. However, a few males with unusual mutations (including distal truncating and hypomorphic missense mutations), and somatic mosaicism have been reported to survive past infancy.

Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: case study and literature review.

Background: The BIG2 protein, coded by ARFGEF2 indirectly assists neuronal proliferation and migration during cortical development. Mutations in ARFGEF2 have been reported as a rare cause of periventricular heterotopia.

Methods: The presence of periventricular heterotopia, acquired microcephaly and suspected recessive inheritance led to mutation analysis of ARFGEF2 in two affected siblings and their healthy consanguineous parents, after mutations in FLNA had been ruled out.

A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands.

NF1 mutations are the underlying cause of neurofibromatosis type 1 (NF1), a neuro-cardio-facio-cutaneous syndrome (NCFC). Because of the clinical overlap between NCFCs, genetic analysis of NF1 is necessary to confirm a clinical diagnosis NF1. This report describes the clinical and genetic findings of 18 years of NF1 molecular diagnostics in the Netherlands.

Considering Fabry, but Diagnosing MPS I: Difficulties in the Diagnostic Process.

Introduction: Recent studies have indicated that a proportion of patients with renal failure, left ventricular hypertrophy, or cryptogenic stroke have sequence variants in their aGal A gene (Fabry disease), which has resulted in an increase in diagnostic activities for this disorder. The diagnostic process for lysosomal storage disorders may result in findings of unknown clinical significance. Here we report such an unexpected outcome.

Complete FXN deletion in a patient with Friedreich's ataxia.

Most patients (98%) with Friedreich's ataxia (FRDA) are homozygous for the GAA repeat expansion in FXN. Only a few compound heterozygous patients with an expanded repeat on one allele and a point mutation or an intragenic FXN deletion on the other allele are described. In a minority of the patients only a heterozygous pattern of the repeat expansion can be detected.

A novel GPR56 mutation causes bilateral frontoparietal polymicrogyria.

Bilateral frontoparietal polymicrogyria is an autosomal recessive inherited human brain malformation with abnormal cortical lamination. The affected cortex appears to consist of numerous small gyri, with scalloping of the cortical-white matter junction. There are associated white matter, brain stem, and cerebellar changes.

Multiplex ligation-depending probe amplification is not suitable for detection of low-grade mosaicism.

'Apparent non-penetrance' occurs in several genetic disorders, including tuberous sclerosis complex and neurofibromatosis type 1: clinically unaffected parents may have multiple affected offspring. Germ line or somatic mosaicism in one of the parents of the index patient is the probable cause and results in an enhanced recurrence risk. Therefore, it is of great importance to use the most sensitive technology for testing DNA of the parents of the index patient for the presence/absence of the familial mutation.

Characterisation of TSC1 promoter deletions in tuberous sclerosis complex patients.

Tuberous sclerosis complex (TSC), an autosomal dominant disorder, is a multisystem disease with manifestations in the central nervous system, kidneys, skin and/or heart. Most TSC patients carry a pathogenic mutation in either TSC1 or TSC2. All types of mutations, including large rearrangements, nonsense, missense and frameshift mutations, have been identified in both genes, although large rearrangements in TSC1 are scarce.

Combined cardiological and neurological abnormalities due to filamin A gene mutation.

Background: Cardiac defects can be the presenting symptom in patients with mutations in the X-linked gene FLNA. Dysfunction of this gene is associated with cardiac abnormalities, especially in the left ventricular outflow tract, but can also cause a congenital malformation of the cerebral cortex. We noticed that some patients diagnosed at the neurogenetics clinic had first presented to a cardiologist, suggesting that earlier recognition may be possible if the diagnosis is suspected.

Mucopolysaccharidosis type IIID: 12 new patients and 15 novel mutations.

Mucopolysaccharidosis III D (Sanfilippo disease type D, MPS IIID) is a rare autosomal recessive lysosomal storage disorder previously described in only 20 patients. MPS IIID is caused by a deficiency of N-acetylglucosamine-6-sulphate sulphatase (GNS), one of the enzymes required for the degradation of heparan sulphate. So far only seven mutations in the GNS gene have been reported.

Enzymatic and molecular strategies to diagnose Pompe disease.

Enzyme replacement therapy for Pompe disease, a neuromuscular disorder characterized by lysosomal glycogen storage due to acid α-glucosidase deficiency, has entered the clinic. There is more than ever a need for early and reliable diagnosis. The objective of this review is to present a critical review of the recent literature on laboratory procedures to diagnose Pompe disease by enzymatic assay and DNA analysis.

Crigler-Najjar syndrome in The Netherlands: identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants.

Crigler-Najjar syndrome (CN), caused by deficiency of UGT isoform 1A1 (UGT1A1), is characterized by severe unconjugated hyperbilirubinemia. In this study we have analyzed 19 CN patients diagnosed in The Netherlands (18) and in Belgium (1), and have identified 14 different UGT1A1 mutations, four of which are novel. Two mutations were present in several unrelated patients, suggesting the presence of two founder effects in The Netherlands.

Movement disorder and neuronal migration disorder due to ARFGEF2 mutation.

We report a child with a severe choreadystonic movement disorder, bilateral periventricular nodular heterotopia (BPNH), and secondary microcephaly based on compound heterozygosity for two new ARFGEF2 mutations (c.2031_2038dup and c.3798_3802del), changing the limited knowledge about the phenotype.

Filamin A mutation, a common cause for periventricular heterotopia, aneurysms and cardiac defects.

Filamin A is an important gene involved in the development of the brain, heart, connective tissue and blood vessels. A case is presented illustrating the challenge in recognising patients with filamin A mutations. The patient, a 71-year-old woman, was known to have heart valve disease and bilateral periventricular nodular heterotopia when she died of a subarachnoid haemorrhage.

A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting.

Background And Aims: In Lynch syndrome, the clinical phenotype in MSH6 mutation families differs from that in MLH1 and MSH2 families. Therefore, MSH6 mutation families are less likely to fulfil diagnostic criteria such as the Amsterdam II criteria (AC II) and the revised Bethesda guidelines (rBG), and will be underdiagnosed. The aim of the present study was to evaluate the contribution of MSH6 gene mutations in families that were analysed for Lynch syndrome in a diagnostic setting.

Cortical brain malformations: effect of clinical, neuroradiological, and modern genetic classification.

Background: Malformations of cortical development (MCDs) are a major source of handicap. Much progress in understanding the genetic causes has been made recently. The number of affected children in whom a molecularly confirmed diagnosis can be made is unclear.

p.[G576S; E689K]: pathogenic combination or polymorphism in Pompe disease?

We discuss four cases of acid alpha-glucosidase deficiency (EC, 3.2.1.

Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification.

The current clinical diagnosis of Von Hippel-Lindau (VHL) disease demands at least one specific [corrected] VHL manifestation in a patient with familial VHL disease, or, in a [corrected] sporadic patient, at least two or more hemangioblastomas or a single hemangioblastoma in combination with a typical visceral lesion. To evaluate this definition, we studied the frequency of germline VHL mutation in three patients groups: (i) multi-organ involvement (classic VHL), (ii) limited VHL manifestations meeting criteria (non-classic VHL) and (iii) patients with VHL-associated tumors not meeting current diagnostic VHL criteria. In addition, we validated multiplex ligation-dependent probe amplification (MLPA) as a rapid and reliable quantitative method for the identification of germline VHL deletions.

Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype.

Background: Pompe disease (acid maltase deficiency, glycogen storage disease type II; OMIM 232300) is an autosomal recessive lysosomal storage disorder characterized by acid alpha-glucosidase deficiency due to mutations in the GAA gene. Progressive skeletal muscle weakness affects motor and respiratory functions and is typical for all forms of Pompe disease. Cardiac hypertrophy is an additional fatal symptom in the classic infantile subtype.