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BACKGROUND: UNC13D, encoding the protein munc13-4, is essential in intracellular trafficking and exocytosis of lytic granules. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a genetically heterogeneous, rare autosomal recessive immune disorder. How mutations affect function of munc13-4 is poorly understood. Since 2006 we genetically identified seven FHL patients with mutations in UNC13D. PROCEDURES: Here, we report for the first time a c.2695C>T (p.Arg899X) mutation in exon 28 of UNC13D in three young unrelated Dutch patients. The mutation causes a premature stop codon and encodes munc13-4(1-899), which lacks the C-terminal C2 domain. Genealogical research and haplotyping of the patient families demonstrated that a single ancestral founder introduced the mutation in the Netherlands. We then characterized the mutant protein phenotypically in cell biological and immunological assays. RESULTS: Munc13-4(1-899) was correctly targeted to CD63-positive secretory lysosomes, although its stability was reduced and dynamic turnover on the granule membrane became uncoupled from receptor signaling. In accord, and in contrast to wild-type munc13-4, ectopically expressed mutant failed to rescue degranulation in cells with silenced endogenous munc13-4. CONCLUSIONS: The functional and clinical data showed that this novel Dutch founder mutation leads to severe early onset of FHL3 due to misfolding and degradation of munc13-4(1-899).

Recent studies have shown that more than 10% of autism cases are caused by de novo structural genomic rearrangements. Given that some heritable copy number variants (CNVs) have been observed in patients as well as in healthy controls, to date little attention has been paid to the potential function of these non-de novo CNVs in causing autism. A normally intelligent patient with autism, with non-affected parents, was identified with a maternally inherited 10 Mb deletion at 13q21.2. Sequencing of the genes within the deletion identified a paternally inherited nonsynonymous amino-acid substitution at position 614 of diaphanous homolog 3 (DIAPH3) (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments showed a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it has a function in brain development. Transfection of Pro614Thr in murine fibroblasts showed a significant reduction in the number of induced filopodia in comparison to the wild-type gene. DIAPH3 is involved in cell migration, axon guidance and neuritogenesis, and is suggested to function downstream of SHANK3. Our findings strongly suggest DIAPH3 as a novel autism susceptibility gene. Moreover, this report of a 'double-hit' compound heterozygote for a large, maternally inherited, genomic deletion and a paternally inherited rare missense mutation shows that not only de novo genomic variants in patients should be taken seriously in further study but that inherited CNVs may also provide valuable information.

Contains fulltext : 153826.pdf (Publisher’s version ) (Closed access) BACKGROUND: Magnesium (Mg(2+)) is an essential ion for cell growth, neuroplasticity and muscle contraction. Blood Mg(2+) levels

Item does not contain fulltext Genomic copy number variations (CNVs) and increased parental age are both associated with the risk to develop a variety of clinical neuropsychiatric disorders such as autism, schizophrenia and bipolar disorder. At the same time, it has been shown that the rate of transmitted de novo single nucleotide mutations is increased with paternal age. To address whether paternal age also affects the burden of structural genomic deletions and duplications, we examined various types of CNV burden in a large population sample from the Netherlands. Healthy participants with parental age information (n = 6,773) were collected at different University Medical Centers. CNVs were called with the PennCNV algorithm using Illumina genome-wide SNP array data. We observed no evidence in support of a paternal age effect on CNV load in the offspring. Our results were negative for global measures as well as several proxies for de novo CNV events in this unique sample. While recent studies suggest de novo single nucleotide mutation rate to be dominated by the age of the father at conception, our results strongly suggest that at the level of global CNV burden there is no influence of increased paternal age. While it remains possible that local genomic effects may exist for specific phenotypes, this study indicates that global CNV burden and increased father's age may be independent disease risk factors.

To investigate familial clustering of schizophrenia, bipolar disorder, and major depressive disorder. Combining data from a psychiatric case registry and Statistics Netherlands provided information on 4,673 affected probands and 18,692 matched population controls. Probands with schizophrenia had relative risks (RRs) for having a sibling with schizophrenia of 3.77 (95% confidence interval (CI): 2.60–5.46) and with bipolar disorder of 1.79 (95% CI: 0.64–4.96) as compared with a reference proband. Probands affected with bipolar disorder have an RR of 6.51 (95% CI: 2.60–16.29) for having a sibling with bipolar disorder and of 1.71 (95% CI: 0.71–4.14) for having a sibling with schizophrenia as compared with a reference proband. Probands affected with major depressive disorder also have increased risk for having a sibling with schizophrenia (RR: 2.04, 95% CI: 1.54–2.72) as compared with a reference proband, which was similar to the risk for having a sibling with major depressive disorder (RR: 1.91, 95% CI: 1.63–2.24) or bipolar disorder (RR: 2.06, 95% CI: 1.18–3.60). Our findings suggest, as previous studies have, that risk across schizophrenia and bipolar disorder is considerably lower (twofold) than within diagnostic entities, whereas for major depressive disorder risk is similar within and across diagnostic entities. Genet Med 2012:14(3):338–341

Item does not contain fulltext Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a substantial heritable component. In pedigrees affected by its familial form, incomplete penetrance is often observed. We hypothesized that this could be caused by a complex inheritance of risk variants in multiple genes. Therefore, we screened 111 familial ALS (FALS) patients from 97 families, and large cohorts of sporadic ALS (SALS) patients and control subjects for mutations in TAR DNA-binding protein (TARDBP), fused in sarcoma/translated in liposarcoma (FUS/TLS), superoxide dismutase-1 (SOD1), angiogenin (ANG) and chromosome 9 open reading frame 72 (C9orf72). Mutations were identified in 48% of FALS families, 8% of SALS patients and 0.5% of control subjects. In five of the FALS families, we identified multiple mutations in ALS-associated genes. We detected FUS/TLS and TARDBP mutations in combination with ANG mutations, and C9orf72 repeat expansions with TARDBP, SOD1 and FUS/TLS mutations. Statistical analysis demonstrated that the presence of multiple mutations in FALS is in excess of what is to be expected by chance (P = 1.57 x 10(-7)). The most compelling evidence for an oligogenic basis was found in individuals with a p.N352S mutation in TARDBP, detected in five FALS families and three apparently SALS patients. Genealogical and haplotype analyses revealed that these individuals shared a common ancestor. We obtained DNA of 14 patients with this TARDBP mutation, 50% of whom had an additional mutation (ANG, C9orf72 or homozygous TARDBP). Hereby, we provide evidence for an oligogenic aetiology of ALS. This may have important implications for the interpretation of whole exome/genome experiments designed to identify new ALS-associated genes and for genetic counselling, especially of unaffected family members.

Contains fulltext : 107990.pdf (Publisher’s version ) (Open Access) Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and ALS. A total of 261 patients with adult-onset sporadic PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands. Sanger sequencing was used to screen these subjects for mutations in the coding regions of superoxide dismutase-1 (SOD1), angiogenin (ANG), fused in sarcoma/translated in liposarcoma (FUS/TLS), TAR DNA-binding protein 43 (TARDBP), and multivesicular body protein 2B (CHMP2B). In our cohort of PMA patients we identified two SOD1 mutations (p.D90A, p.I113T), one ANG mutation (p.K17I), one FUS/TLS mutation (p.R521H), one TARDBP mutation (p.N352S), and one novel CHMP2B mutation (p.R69Q). The mutation frequency of these genes was similar in sporadic PMA (2.7%) and ALS (2.0%) patients, and therefore, our findings demonstrate a genetic overlap between apparently sporadic PMA and ALS.

We measured the association between paternal age and schizophrenia (SCZ), autism spectrum disorders (ASD), major depressive disorder (MDD), and bipolar disorder (BPD) in the Dutch population.In total, 14231 patients and 56924 matched controls were collected and analyzed for an association with paternal age by logistic regression.ASD is significantly associated with increased paternal age: Older fathers40 years of age have a 3.3 times increased odds of having a child with ASD compared to young fathers20 years of age. SCZ has significant associations for fathers aged35 years (OR=1.27, 95% Confidence Interval: 1.05 and 1.53). For MDD, both younger and older fathers have increased odds. No association was found for BPD.The effects of paternal age as a risk factor are different for ASD and SCZ on one hand, and the affective disorders on the other hand. Different types of association might indicate different biological or psychosocial mechanisms. Late paternity (associated with predispositions to psychiatric disorders) seems the most probable explanation for the association with paternal age.

Approximately 90% of amyotrophic lateral sclerosis (ALS) cases are sporadic (SALS), but 10% are familial (FALS). Mutations in SOD1, Alsin , Dynactin , SETX , DJ-1 , VAPB , and TDP-431 have been reported (table e-1 on the Neurology ® Web site at www.neurology.org). After the identification of sequence variation VEGF in patients with ALS, mutations in another angiogenic gene ( ANG ) were identified in SALS and FALS.2,3 Studies in other populations have identified ANG mutations in patients with ALS, but also in healthy controls. This suggests that not all mutations are pathogenic.3,4 ### Methods. A total of 39 unrelated FALS patients, negative for SOD1 mutations, were screened for ANG mutations. This study was approved by the local ethics committee and participants provided informed consent. DNA was isolated from venous blood and ANG mutation analysis was performed as described in appendix e-1. A total of 275 unrelated, healthy controls were taken from a prospective population-based study on ALS in The Netherlands and were also screened.5 PMut (http://mmb2.pcb.ub.es:8080/PMut/) was used to predict the impact of an amino acid substitution on the structure and function of the protein. ### Results. We identified one mutation in one patient (122 A>T) (figure, A), leading to an amino acid substitution of lysine to isoleucine (K17I) (figure, B). PMut analysis predicted this mutation to be pathogenic. Sequence alignments of ANG in different species …

Benign recurrent intrahepatic cholestasis (BRIC) is a rare disorder characterized by recurrent episodes of cholestasis without permanent liver damage. Familial and sporadic cases have been described. Based on existing evidence, both autosomal-recessive and autosomal-dominant inheritance have been considered. We describe a large Dutch pedigree with 4 patients, strongly suggesting autosomal-recessive inheritance.