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Aim: To investigate the interdependence between risk factors associated with long-term intellectual development in individuals with tuberous sclerosis complex (TSC).Method: The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of individuals with TSC. In phase 1 of the study, baseline measures of intellectual ability, epilepsy, cortical tuber load, and mutation were obtained for 125 children (63 females, 62 males; median age=39mo). In phase 2, at an average of 8 years later, intellectual abilities were estimated for 88 participants with TSC and 35 unaffected siblings. Structural equation modelling was used to determine the risk pathways from genetic mutation through to IQ at phase 2.Results: Intellectual disability was present in 57% of individuals with TSC. Individuals without intellectual disability had significantly lower mean IQ compared to unaffected siblings, supporting specific genetic factors associated with intellectual impairment. Individuals with TSC who had a slower gain in IQ from infancy to middle childhood were younger at seizure onset and had increased infant seizure severity. Structural equation modelling indicated indirect pathways from genetic mutation, to tuber count, to seizure severity in infancy, through to IQ in middle childhood and adolescence.Interpretation: Early-onset and severe epilepsy in the first 2 years of life are associated with increased risk of long-term intellectual disability in individuals with TSC, emphasizing the importance of early and effective treatment or prevention of epilepsy.What This Paper Adds: Intellectual disability was present in 57% of individuals with tuberous sclerosis complex (TSC). Those with TSC without intellectual disability had significantly lower mean IQ compared to unaffected siblings. Earlier onset and greater severity of seizures in the first 2 years were observed in individuals with a slower gain in intellectual ability. Risk pathways through seizures in the first 2 years predict long-term cognitive outcomes in individuals with TSC. [ABSTRACT FROM AUTHOR]

Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported. [ABSTRACT FROM AUTHOR]

Many mRNAs carrying mutations that are predicted to encode a truncated protein are subject to a mechanism known as nonsense-mediated mRNA decay (NMD), which results in reduced levels of mutant transcript. Tuberous sclerosis (TSC), an autosomal dominant neurocutaneous disorder with mutations in either of two genes, TSC1 or TSC2, requires comprehensive screening of both genes for molecular diagnosis. Virtually all TSC1 mutations are predicted to truncate the protein product. Coding and newly identified 3′ untranslated region polymorphisms in TSC1 were used to develop a transcript imbalance assay to investigate TSC1 transcript levels in patients. This approach allowed the correct identification of six out of seven TSC1 patients tested blind from a panel of TSC1 and TSC2 patients, with no false positives. The extent of NMD in TSC1 was found to correlate with each individual mutation regardless of intra-familial variation in clinical features and with no strong evidence for positional bias. NMD in TSC1 was more pronounced in cultured cells than in RNA prepared directly from peripheral lymphocytes (in which novel splicing of exon 5 was observed). The advent of a dense SNP map of transcribed regions of the genome may allow a similar transcript imbalance assay in the assessment of candidate genes for diseases whose causes are still unknown. [ABSTRACT FROM AUTHOR]

A correction to the article "CASK Mutations Are Frequent in Males and Cause X-Linked Nystagmus and Variable XLMR Phenotypes," by Anna Hackett and colleagues that was published in the December 23, 2009 issue is presented.

The Ehlers-Danlos syndrome (EDS) is a heterogeneo US group of inherited connective tissue disorders in which cutaneous fragility and ligamentous laxity often combine with vascular, gastrointestinal, and skeletal deformities. There is considerable phenotypic overlap between the more common fonas of EDS (types I and II), in which specific molecular defects have not yet been identified. Recently, genetic linkage has been demonstrated between the COL5A1 gene, which encodes the α1 chain of type V collagen, and EDS type II in a large British kindred. Using a polymorphic intragenic simple sequence repeat at the COL5A1 locus, we now demonstrate tight linkage to EDS type I/II in a three-generation family, giving a LOD score (log10 of the odds for linkage) of 4.07 at zero recombination. The variation in expression in this family suggests that EDS types I and II are allelic, and the linkage data support the hypothesis that mutation in COL5A1 can cause both phenotypes. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a leading cause of vision loss; there is strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor-H-like 1 (FHL-1), and five factor-H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about how AMD-associated variants at this locus might influence FHL-1 and FHR protein concentrations. We have used a bespoke targeted mass-spectrometry assay to measure the circulating concentrations of all seven complement regulators and demonstrated elevated concentrations in 352 advanced AMD-affected individuals for all FHR proteins (FHR-1, p = 2.4 × 10 -10 ; FHR-2, p = 6.0 × 10 -10 ; FHR-3, p = 1.5 × 10 -5 ; FHR-4, p = 1.3 × 10 -3 ; FHR-5, p = 1.9 × 10 -4 ) and FHL-1 (p = 4.9 × 10 -4 ) when these individuals were compared to 252 controls, whereas no difference was seen for FH (p = 0.94). Genome-wide association analyses in controls revealed genome-wide-significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian-randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4, and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how genetically driven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD., Competing Interests: Declaration of interests P.N.B., S.J.C., and R.D.U. are inventors named in patent applications that describe the use of complement inhibitors for therapeutic purposes and the use of circulating complement-protein measurement for patient stratification and are co-founders of and shareholders in Complement Therapeutics, a company that focuses on the development of complement-targeted therapeutics, including for AMD. The remaining authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Infantile spasms (IS) have long been suspected to be a risk factor for impairment in intellectual development, but there are no controlled, prospective longitudinal data in well-characterized conditions to confirm this suspicion. We tested the hypothesis in a longitudinal study of children with tuberous sclerosis (TS), who have a high risk of developing IS., Methods: Eleven infants with TS were recruited and studied longitudinally using the Mullen Scales of Early Learning. Seizure histories were assessed using a structured parent interview and by review of medical notes. Intellectual development was examined in relation to the onset and length of exposure to IS and other types of seizures., Results: Six children developed IS and five children developed other types of seizure disorders. Among those that developed IS, estimated mean IQ dropped significantly (nonparametric test for trend p = 0.002) from 92 (prior to onset of spasms) to 73 (after exposure to IS for a month or less) and 62 (after exposure to IS for more than a month). By contrast, there was no significant drop in estimated IQ among the five infants exposed to other types of seizure disorders (nonparametric test for trend p = 0.9). All six children exposed to infantile spasms developed clinically significant intellectual impairment., Significance: These data provide the first clear evidence of clinically significant, dose dependent, impairment in intellectual development following exposure to infantile spasms. The mechanisms underlying this developmental impairment and methods for preventing it require in depth study., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Background: Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking., Methods: To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry., Results: In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies., Conclusion: The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.

Purpose: To examine the role of complement factor D (CFD) in age-related macular degeneration (AMD) by analysis of genetic association, copy number variation, and plasma CFD concentrations., Methods: Single nucleotide polymorphisms (SNPs) in the CFD gene were genotyped and the results analyzed by binary logistic regression. CFD gene copy number was analyzed by gene copy number assay. Plasma CFD was measured by an enzyme-linked immunosorbent assay., Results: Genetic association was found between CFD gene SNP rs3826945 and AMD (odds ratio 1.44; P = 0.028) in a small discovery case-control series (462 cases and 325 controls) and replicated in a combined cohorts meta-analysis of 4765 cases and 2693 controls, with an odds ratio of 1.11 (P = 0.032), with the association almost confined to females. Copy number variation in the CFD gene was identified in 13 out of 640 samples examined but there was no difference in frequency between AMD cases (1.3%) and controls (2.7%). Plasma CFD concentration was measured in 751 AMD cases and 474 controls and found to be elevated in AMD cases (P = 0.00025). The odds ratio for those in the highest versus lowest quartile for plasma CFD was 1.81. The difference in plasma CFD was again almost confined to females., Conclusions: CFD regulates activation of the alternative complement pathway, which is implicated in AMD pathogenesis. The authors found evidence for genetic association between a CFD gene SNP and AMD and a significant increase in plasma CFD concentration in AMD cases compared with controls, consistent with a role for CFD in AMD pathogenesis.