Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene.

Predicting the pathogenicity of biallelic missense variants can be challenging. Here, we use a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes. We follow three missense variants with a complete deficit of homozygosity and find that their pathogenic effect in homozygous state ranges from severe childhood disease to early embryonic lethality. One of these variants is in CPSF3, a gene not previously linked to disease. From a set of clinically sequenced Icelanders, and by sequencing archival samples targeted through the Icelandic genealogy, we find four homozygous carriers. Additionally, we find two homozygous carriers of Mexican descent of another missense variant in CPSF3. All six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. Here, we show how the absence of certain homozygous genotypes from a large population set can elucidate causes of previously unexplained recessive diseases and early miscarriage.

Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort.

BACKGROUND: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. METHODS: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. RESULTS: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. CONCLUSIONS: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.

[Acute ischemic stroke in female adolescent - Case report]. / Brátt blóðþurrðarslag hjá unglingsstúlku Sjúkratilfelli.

During soccer practice a fifteen year old girl experienced a sudden onset of pain in the left side of her neck and collapsed. Upon arrival at the emergency room she had right hemiparesis and expressive aphasia. On CT angiography a left carotid arterial dissection was suspected. Symptoms improved during the first three days but worsened again on the fourth and a CT scan showed an ischemic area in the brain. Conventional angiography showed decreased perfusion in the left middle cerebral artery but no evidence of dissection or thrombus. The most likely diagnosis was thought to be reverse cerebral vasoconstriction syndrome and the girl was treated with calcium channel inhibitors. Here we report the case and review the literature.

Large-scale whole-genome sequencing of the Icelandic population.

Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.

A de novo 1.13 Mb microdeletion in 12q13.13 associated with congenital distal arthrogryposis, intellectual disability and mild dysmorphism.

A girl presented with congenital arthrogryposis, intellectual disability and mild bone-related dysmorphism. Molecular workup including the NimbleGen Human CGH 2.1M platform revealed a 1.13 Mb de novo microdeletion on chromosome 12q13.13 of paternal origin. The deletion contains 33 genes, including AAAS, AMRH2, and RARG genes as well as the HOXC gene cluster. At least one gene, CSAD, is expressed in fetal brain. The deletion partially overlaps number of reported benign CNVs and pathogenic duplications. This case appears to represent a previously unknown microdeletion syndrome and possibly the first description in humans of a disease phenotype associated with copy loss of HOXC genes.

Prevalence of recurrent symptoms and their association with epilepsy and febrile seizure in school-aged children: a community-based survey in Iceland.

We determined the prevalence of common recurrent symptoms in a community-based study of children and investigated whether these symptoms were associated with epilepsy and febrile seizure. A questionnaire was developed and sent to parents of all children attending school in the Reykjavik school district, grades 1-10. The questions assessed personality traits, headache, epilepsy, febrile seizure, and recurrent symptoms. Of the 13,044 questionnaires distributed, 10,578 were returned (81%). We analyzed the subset of 9679 (91%) questionnaires with complete information on relevant factors. The prevalence of epilepsy was 7.7/1000; febrile seizures were reported in 5.1% of children. Prevalence estimates of recurrent symptoms were similar to the published literature. In our cohort, recurrent dizzy spells and recurrent visual disturbances were associated with epilepsy after adjustment for age, migraine and febrile seizure. This association could reflect, only in part, the occurrence of auras in children with epilepsy.

[Rickets in a child]. / Beinkrom hja barni.

Vitamin D is necessary for normal bone growth. Deficiency of vitamin D can lead to rickets in children and osteomalacia in adults. It is difficult to reach the recommended daily dose of vitamin D in children without cod liver oil or other vitamin D supplementation. Several cases of rickets have been diagnosed in Iceland the past few years. Studies suggest a worldwide increase in the prevalence of the disorder. We report on a girl who was diagnosed with rickets at the age of 27 months. She received inadequate amounts of vitamin D supplementation in the form of AD drops and cod liver oil. Because of food allergy she was on a restricted diet which limited her intake of dietary vitamin D. After diagnosis, she received a high-dose vitamin D therapy (Stoss therapy) which corrected the deficiency. Key words: rickets, food allergy, vitamin D.

Risk of autism spectrum disorders after infantile spasms: a population-based study nested in a cohort with seizures in the first year of life.

PURPOSE: No population-based study has investigated the risk of autism spectrum disorders (ASDs) in children after unprovoked seizures with onset in the first year of life. Our objective was to determine whether infantile spasms were related to risk of ASD as compared to unprovoked seizures with onset in the first year of life after adjusting for symptomatic origin of seizures. METHODS: This is a population-based case-control study nested in a cohort of children with unprovoked seizures in the first year of life. The cohort comprised 95 children, 34 boys and 61 girls. Cases were defined as children with ASD, controls were without ASD, and exposure was a history of infantile spasms. The Mantel-Haenszel test and logistic regression were used to calculate the odds ratio (OR) and 95% confidence intervals (CI). RESULTS: The crude OR for ASD associated with infantile spasms was 5.53 (95% CI 1.25-23.06). Stratification on age and gender did not change the OR. The OR for ASD associated with infantile spasms adjusted for symptomatic seizures was 1.55 (95% CI 0.33-7.37), while the OR for ASD associated with symptomatic seizures adjusted for infantile spasms was 8.73 (95% CI 1.88-40.54). Restriction to mental age 24 months or higher yielded higher ORs. DISCUSSION: Infantile spasms predicted high risk for ASD, but this was to a large extent explained by the association of ASD with symptomatic origin of seizures.

Autism spectrum disorders in children with a history of infantile spasms: a population-based study.

The objective of this article is to describe autistic spectrum disorders in children diagnosed with infantile spasms in the first year of life. The source of data was the records of all 3 pediatric departments in Iceland. Twenty children born between 1981 and 1998 who had infantile spasms were invited to participate. When appropriate, the parents of these children were asked to complete the Social Communication Questionnaire. Children scoring 10 points or higher on the questionnaire were selected for further examination using the Autism Diagnostic Interview- Revised and either the Autism Diagnostic Observation Schedule or the Childhood Autism Rating Scale. All participants were given appropriate cognitive tests or measures of adaptive behavior. The parents of 17 children (10 boys, 7 girls) agreed to participate in the study. Age at assessment ranged from 5 to 19 years with a mean age of 11 years and 6 months. Fourteen children had at least one neurodevelopmental disorder. Six (6/17), or 35.3%, were diagnosed with autism spectrum disorder (3 boys, 3 girls), five of these had a history of symptomatic infantile spasms, and four were profoundly mentally retarded (IQ/DQ<20). If the diagnosis of autism spectrum disorder was restricted to children with a developmental age of 24 months or more (3 cases), the prevalence was 17.6%. The estimates found in this study exceed the estimated prevalence of autism spectrum disorder in the general population.

Co-occurrence of major depression or suicide attempt with migraine with aura and risk for unprovoked seizure.

We hypothesized and found that the co-occurrence of migraine with aura (MA) with major depression (MD) or with suicide attempt (SA) increases the risk for developing unprovoked seizure more than these conditions alone. Number of conditions showed a linear relationship to seizure risk. This may reflect a new condition cluster defined by MA, MD, SA and unprovoked seizures. Identifying the biological underpinnings this cluster may affect clinical diagnosis and treatment.

Autism spectrum disorders in children with seizures in the first year of life - a population-based study.

PURPOSE: To describe autistic spectrum disorders (ASDs) in a cohort of children with history of unprovoked seizures other than infantile spasms in the first year of life. METHODS: The source of data was computer records from all the three pediatric departments in Iceland. Children diagnosed 1982-2000 with unprovoked seizures with onset between 28 days and 12 months of age (N = 102) were invited to participate in a study. Children with known developmental disorders and those whose parents had concerns regarding their child's development or behavior were investigated for possible ASD. Parents were asked to complete the Social Communication Questionnaire and children scoring 10 points or higher were further examined with the Autism Diagnostic Interview-Revised and observational measures. RESULTS: Eighty-four children (82.4%), 28 boys and 56 girls, participated in the study and 36.9% (31/84) were investigated for possible ASD. Twenty-four (28.6%) had at least one neurodevelopmental disorder, 14.3% had mental retardation (MR), and six (7.1%) were diagnosed with ASD, all of whom also had MR and three of whom had congenital brain abnormalities. CONCLUSION: These results suggest that the estimated prevalence of ASD is higher in children with history of seizure in the first year of life than it is in the general population. There are indications that support the view that children with ASD and history of seizure in the first year of life have higher prevalence of congenital brain abnormalities and are more often female, than other children with ASD.

Depression and suicide attempt as risk factors for incident unprovoked seizures.

Major depression has been shown to increase the risk for development of epilepsy, but prior studies have not evaluated whether this is due to specific symptoms of depression. We conducted a population-based case-control study of all newly diagnosed unprovoked seizures among Icelandic children and adults aged 10 years and older to test the hypothesis that major depression is a risk factor for developing unprovoked seizure and epilepsy, and to address whether specific symptoms of depression account for this increased risk. Cases were matched to the next two same sex births from the population registry. Using standardized interviews, we ascertained symptoms of major depression to make a Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) diagnosis. A history of major depression was 1.7-fold more common among cases than among controls (95% confidence interval, 1.1-2.7). A history of attempted suicide was 5.1-fold more common among cases than among controls (95% confidence interval, 2.2-11.5). Attempted suicide increased seizure risk even after adjusting for age, sex, cumulative alcohol intake, and major depression or number of symptoms of depression. Major depression and attempted suicide independently increase the risk for unprovoked seizure. These data suggest that depression and suicide attempt may be due to different underlying neurochemical pathways, each of which is important in the development of epilepsy.

Migraine with aura is a risk factor for unprovoked seizures in children.

OBJECTIVE: Migraine is associated with epilepsy, but the time order and nature of the relationship are unclear. We conducted a population based case control study to clarify the time order to determine whether migraine is a risk factor for epilepsy. METHODS: Migraine symptoms were evaluated in a population-based case-control study of all incident epilepsy in Icelandic children and in matched controls (next two same sex births in the country). RESULTS: Migraine was associated with a fourfold increased risk for developing epilepsy, an association explained by migraine with aura (odds ratio, 8.1; 95% confidence interval, 2.7-24.3). Migraine without aura did not increase risk for epilepsy. INTERPRETATION: Children with migraine with aura have a substantial increased risk to develop subsequent epilepsy. This finding is consistent with the hypothesis that migraine with aura and migraine without aura may be different disorders.

Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study.

BACKGROUND: No population-based incidence studies of epilepsy have studied syndrome classification from the outset. We prospectively studied the incidence of a single unprovoked seizure and epilepsy in the population of Iceland, and applied the syndrome classification endorsed by the International League Against Epilepsy to this population. METHODS: We used a nationwide surveillance system to prospectively identify all residents of Iceland who presented with a first diagnosis of a single unprovoked seizure or epilepsy between December 1995 and February 1999. All cases were classified by seizure type, cause or risk factors, and epilepsy syndrome. RESULTS: The mean annual incidence of first unprovoked seizures was 56.8 per 100,000 person-years, 23.5 per 100,000 person-years for single unprovoked seizures, and 33.3 per 100,000 person-years for epilepsy (recurrent unprovoked seizures). Incidence was similar in males and females. Partial seizures occurred in 40% and a putative cause was identified in 33%. Age-specific incidence was highest in the first year of life (130 per 100,000 person-years) and in those 65 years and older (110.5 per 100,000 person-years). Using strict diagnostic criteria for epilepsy syndromes, 58% of cases fell into non-informative categories. Idiopathic epilepsy syndromes were identified in 14% of all cases. INTERPRETATION: Findings are consistent with incidence studies from developed countries. Although the epilepsy syndrome classification might be useful in tertiary epilepsy centers, it has limited practicality in population studies and for use by general neurologists.

Socioeconomic status is a risk factor for epilepsy in Icelandic adults but not in children.

PURPOSE: Two earlier population-based studies provide conflicting information on the association between low socioeconomic status (SES) and risk for epilepsy. Seizure etiologies (e.g., head injury, stroke) associated with low SES were not addressed in prior analyses. We assess the relation between SES indices and incident epilepsy separately for children and adults and in subgroups defined by seizure etiology. METHODS: In this population-based case-control study, a surveillance system identified incident unprovoked seizure or first diagnosis of epilepsy throughout Iceland (n = 418). Controls were selected from the population registry as the next two same-sex births alive, residing in Iceland at the time of the index seizure, and without a history of unprovoked seizure on the date of the case's incident seizure (n = 835). The odds ratio measured the association between SES and epilepsy. RESULTS: An association was found between epilepsy and SES among adults, but not among children. Among adults, low education was associated with an increased risk for epilepsy [odds ratio (OR), 2.29; 95% confidence interval (CI), 1.21-4.34), and home ownership was protective (OR, 0.63; 95% CI, 0.43-0.92). When analyses were repeated by seizure etiology, this association remained only in the group with epilepsy of unknown cause, even after adjusting for alcohol consumption. CONCLUSIONS: Low SES, indexed by low education or lack of home ownership, is a risk factor for epilepsy in adults, but not in children, suggesting a cumulative effect of SES on risk for epilepsy. This association is not explained by established risk factors for epilepsy (e.g., head injury, stroke). We find no evidence of a downward social drift among cases whose parents had epilepsy.

ADHD as a risk factor for incident unprovoked seizures and epilepsy in children.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) occurs more frequently than expected in prevalent cohorts with epilepsy. The association has been attributed to the epilepsy or its treatment, although it is impossible to determine in previous studies which condition occurs first. OBJECTIVES: To conduct a population-based case-control study of all newly diagnosed unprovoked seizures among Icelandic children younger than 16 years to address the question of time order. DESIGN: Children with seizures were matched to the next 2 same-sex births from the population registry. The Diagnostic Interview Schedule for Children was used to make a DSM-IV diagnosis of ADHD in a standardized fashion among cases and controls aged 3 to 16 years. RESULTS: A history of ADHD was 2.5-fold more common among children with newly diagnosed seizures than among control subjects (95% confidence interval [CI], 1.1-5.5). The association was restricted to ADHD predominantly inattentive type (odds ratio [OR], 3.7; 95% CI, 1.1-12.8), not ADHD predominantly hyperactive-impulsive type (OR, 1.8; 95% CI, 0.6-5.7) or ADHD combined type (OR, 2.5; 95% CI, 0.3-18.3). Seizure type, etiology, sex, or seizure frequency at diagnosis (1 or >1) did not affect findings. CONCLUSION: Attention-deficit/hyperactivity disorder occurs more often than expected before unprovoked seizures, suggesting a common antecedent for both conditions.