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Abstract. Expansion of the FRAXE CCG repeat to a full mutation is associated with methylation and transcriptional silencing of the FMR2 gene, and as a consequence, mild-toborderline mental retardation. FMR2 is a member of a family of four proteins, AF4, LAF4, FMR2, and AF5q31. The proteins associated with this family localize to the cell nucleus. Various regions of FMR2, and each of the other members of the protein family, were cloned and analyzed for transcription activation in yeast and mammalian cells. In both yeast and mammalian cells, FMR2 showed strong transcription activation. AF4 activation potential was several-fold lower. Interestingly, isoforms of both FMR2 and LAF4 lacking exon 3 activated transcription better than the larger isoforms containing exon 3. Compared with the other members of the family, activation by FMR2 was the strongest. Our results show that FMR2 is a potent transcription activator and that its function is conserved. Elucidation of the function of the FMR2 protein as a transcription activator may place FMR2 within the molecular signalling pathways involved in nonspecific X-linked mental retardation (MRX). [ABSTRACT FROM AUTHOR]

We report two families with Brunner syndrome living in one state of Australia. The first family had a predicted protein-truncating variant of monoamine oxidase A (MAOA) (p.S251KfsX2). Affected males had mild intellectual disability (ID), obsessive behaviour, limited friendships and were introverted and placid during clinical interview. The family disclosed episodic explosive aggression after a diagnosis was made. The second family had a missense variant in MAOA (p.R45W). Affected males had borderline-mild ID, attention deficit disorder and limited friendships. One had a history of explosive aggression in childhood and episodic symptoms of flushing, headaches and diarrhoea. Their carrier mother had normal intelligence but similar episodic symptoms. Characteristic biochemical abnormalities included high serum serotonin and urinary metanephrines and low urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA). Symptomatic individuals in the second family had particularly high serotonin levels, and treatment with a serotonin reuptake inhibitor and dietary modification resulted in reversal of biochemical abnormalities, reduction of 'serotonergic' symptoms and behavioural improvement. Brunner syndrome should be considered as a cause of mild ID with paroxysmal behavioural symptoms. It can be screened for with serum/urine metanephrine and serotonin measurement. Cautious treatment with a serotonin reuptake inhibitor, dietary modifications and avoidance of medications contraindicated in patients on monoamine oxidase inhibitors can improve symptoms. [ABSTRACT FROM AUTHOR]

Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ∼ 2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score.Ten de novo mutations in three previously identified disease genes (TUBA!A (n = 2), SCN8A (n = 1) and KDM5C (n = 1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome χ in two known disease genes, LI CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes. [ABSTRACT FROM AUTHOR]

We describe an 36week male who was born with mild hypotonia and subsequently found to have severe developmental delay. There is also reported optic nerve atrophy. Serum creatine kinase (CK) was 5582. MRI of the brain demonstrated periventricular white matter loss, ventriculomegaly, and a thin corpus callosum. His muscle biopsy demonstrated severe non-specific dystrophic changes. Staining with VIA4-1, however, demonstrated normal levels of glycosylated alpha-dystroglycan, and genetic testing for genes known to cause Walker-Warburg Syndrome (WWS) was negative. Whole exome sequencing was performed, which demonstrated compound heterozygous mutations in GOSR2, including a previously described mutation c.430G>T as well as a novel splice site mutation c.336+1G>A. Previous reports have described homozygous c.430G>T mutations as causative of progressive myoclonus epilepsy (PME), a syndrome characterized by myoclonus, seizures, and progressive cognitive decline. Patients with this GOSR2 mutation also have areflexia, tremors, ataxia, and mildly elevated CK levels, suggesting a possible subclinical myopathy. Muscle biopsies on these PME patients, however, have been normal. Interestingly, at 28months of age, the patient began to experience clinical seizures with one episode of status epilepticus. GOSR2 encodes for a SNARE involved with protein transport from the endoplasmic reticulum to the trans-Golgi apparatus. Our studies suggest that GOSR2 may play a role in the transport of critical membrane glycoprotein complexes of myocytes. [Copyright &y& Elsevier]

A letter to the editor is presented on CCDC22 as a new X-linked intellectual disability (XLID) candidate gene for targeted sequencing studies.

Fullston T, Finnis M, Hackett A, Hodgson B, Brueton L, Baynam G, Norman A, Reish O, Shoubridge C, Gecz J. Screening and cell-based assessment of mutations in the Aristaless-related homeobox ( ARX) gene. ARX mutations cause a diverse spectrum of human disorders, ranging from severe brain and genital malformations to non-syndromic intellectual disability (ID). ARX is a transcription factor with multiple domains that include four polyalanine (pA) tracts, the first two of which are frequently expanded by mutations. We progressively screened DNA samples from 613 individuals with ID initially for the most frequent ARX mutations (c.304ins(GCG)7'expansion' of pA1 and c.429_452dup 'dup24bp' of pA2). Five hundred samples without pA1 or pA2 mutations had the entire ARX ORF screened by single stranded polymorphism conformation (SSCP) and/or denaturing high pressure liquid chromatography (dHPLC) analysis. Overall, eight families with six mutations in ARX were identified (1.31%): five duplication mutations in pA2 (0.82%) with three new clinical reports of families with the dup24bp and two duplications larger than the dup24bp mutation discovered (dup27bp, dup33bp); and three point mutations (0.6%), including one novel mutation in the homeodomain (c.1074G>T). Four ultraconserved regions distal to ARX (uc466-469) were also screened in a subset of 94 patients, with three unique nucleotide changes identified in two (uc466, uc467). The subcellular localization of full length ARX proteins was assessed for 11 variants. Protein mislocalization increased as a function of pA2 tract length and phenotypic severity, as has been previously suggested for pA1. Similarly, protein mislocalization of the homeodomain mutations also correlated with clinical severity, suggesting an emerging genotype vs cellular phenotype correlation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses the two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients.

Background/Aims: Two half-brothers with similar malformed genitals, who both inherited a maternally derived t(X;5)(q13;p15) translocation, have a phenotype consistent with partial androgen sensitivity syndrome. The aim was to identify the gene disrupted by the X chromosome breakpoint. Methods: The breakpoint was localized using fluorescence in situ hybridization to metaphase spreads of the translocation. Results: The break-point on the X chromosome of the X;5 translocation was localized to a 30-kb region. This region does not contain any identified genes or transcripts. However, the break- point is approximately 134 kb from the 5' end of the androgen receptor (AR) gene. Conclusions: Genetic defects of the AR gene are collectively called androgen insensitivity syndrome and include a range of phenotypes from normal males, often with associated sterility, to XY females. The phenotype seen in the males with the t(X;5) is consistent with this syndrome. The analysis of the chromosomal abnormality suggests that this translocation may remove one or more upstream regulatory elements of the AR gene that are essential for its normal expression and its role in typical external masculinization. [ABSTRACT FROM AUTHOR]

Turner G, Lower KM, White SM, Delatycki M, Lampe AK, Wright M, Clayton-Smith J, Kerr B, Schelley S, Hoyme HE, De Vries BBA, Kleefstra T, Grompe M, Cox B, Gecz J, Partington M. The clinical picture of the Börjeson–Forssman–Lehmann syndrome in males and heterozygous females with PHF6 mutations. The usual description of the Börjeson–Forssman–Lehmann syndrome (BFLS) is that of a rare, X-linked, partially dominant condition with severe intellectual disability, epilepsy, microcephaly, coarse facial features, long ears, short stature, obesity, gynecomastia, tapering fingers, and shortened toes. Recently, mutations have been identified in the PHF6 gene in nine families with this syndrome. The clinical history and physical findings in the affected males reveal that the phenotype is milder and more variable than previously described and evolves with age. Generally, in the first year, the babies are floppy, with failure to thrive, big ears, and small external genitalia. As schoolboys, the picture is one of learning problems, moderate short stature, with emerging truncal obesity and gynecomastia. Head circumferences are usually normal, and macrocephaly may be seen. Big ears and small genitalia remain. The toes are short and fingers tapered and malleable. In late adolescence and adult life, the classically described heavy facial appearance emerges. Some heterozygous females show milder clinical features such as tapering fingers and shortened toes. Twenty percent have significant learning problems, and 95% have skewed X inactivation. We conclude that this syndrome may be underdiagnosed in males in their early years and missed altogether in isolated heterozygous females. [ABSTRACT FROM AUTHOR]

Presents a study which determined the spectrum of novel mutations in the spondyloepiphyseal dysplasia tarda (SEDL) gene in unrelated patients with SEDL, a radiologically distinct skeletal dysplasia that affect the vertebrae and epiphyses. Methods; Results; Discussion.