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The filamin A gene (FLNA) on Xq28 encodes the filamin A protein. Mutation in FLNA causes a wide spectrum of disease including skeletal dysplasia, neuronal migration abnormality, cardiovascular malformation, intellectual disability and intestinal obstruction. Recently, childhood-onset interstitial lung disease associated with a range of FLNA mutations has been recognised and reported. We document our personal experience of this emerging disorder and compile a comprehensive overview of clinical features and molecular changes in all identifiable published cases. Reviewing the emerging dataset, we underline this unanticipated phenotypic consequence of pathogenic FLNA mutation-associated pulmonary disease.Conclusion: From the emerging data, we suggest that while reviewing complex cases with a sustained oxygen requirement against a clincial background of cardiac concerns or intestinal obstruction to have a high index of suspicion for FLNA related pathology and to instigate early MRI brain scan and FLNA mutation analysis.What is Known:• FLNA gene on Xq28 encodes the filamin A protein and mutation therein is associated with variable phenotypes depending on its nature of mutation.• Loss-of-function mutation of filamin A is associated with X-linked inherited form of periventricular nodular heterotopia with or without epilepsy with most individuals affected being female. There is a recently recognised associated respiratory phenotype.What is New:• The respiratory phenotype in the form of childhood interstitial lung disease is a recently recognised clinical consequence of loss-of-function FLNA mutation.• Rare male patients with loss-of-function FLNA mutation-associated lung disease with residual protein function can survive into infancy with a severe form of the phenotype.

Craniofrontonasal syndrome (CFNS) is an X-linked malformation syndrome with variable phenotype that is caused by mutations in the ephrin-B1 gene ( EFNB1 ). Over 50% of EFNB1 mutations result in premature termination codons that may elicit mRNA degradation by the nonsense-mediated decay pathway. To assess the effects of various mutations at the transcript level, expression of EFNB1 mRNA was studied by RT-PCR in fibroblast cultures established from CFNS female patients. Compared to the wild-type and two missense mutation alleles, severe depletion of transcripts was observed for mutant alleles harbouring either splice site mutation c.407-2A>T at the exon 2/3 boundary or frameshift mutation c.377_384delTCAAGAAG in exon 2. In contrast, escape from mRNA decay was observed for mutation c.614_615delCT, which generates a premature termination codon close to the 3′-end of the penultimate exon 4 disobeying the ‘50–55 bp’ rule. These results suggest differential degradation of mutant EFNB1 transcripts by the nonsense-mediated mRNA decay pathway. Although the clinical phenotypes of the patients were not highly suggestive of a phenotype–genotype correlation, the two female patients were diagnosed with diaphragmatic hernia harbouring putative ephrin-B1 truncating mutations. Previously, disease manifestation in heterozygous females had been attributed mainly to cellular interference of divergent cell populations expressing wild-type or mutant EFNB1 , depending on the pattern of X-inactivation. Upon clonal expansion of patient cells with either the wild-type or mutant EFNB1 on the active X-chromosome, we were able to separate mutant and wild-type EFNB1 -expressing cells in vitro , further supporting the concept of cellular interference in CFNS.

Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta which can occur sporadically, as an autosomal dominant condition, or as one component of Williams syndrome. SVAS is caused by translocations, gross deletions and point mutations that disrupt the elastin gene (ELN) on 7q11.23. Functional hemizygosity for elastin is known to be the cause of SVAS in patients with gross chromosomal abnormalities involving ELN. However, the pathogenic mechanisms of point mutations are less clear. One hundred patients with diagnosed SVAS and normal karyotypes were screened for mutations in the elastin gene to further elucidate the molecular pathology of the disorder. Mutations associated with the vascular disease were detected in 35 patients, and included nonsense, frameshift, translation initiation and splice site mutations. The four missense mutations identified are the first of this type to be associated with SVAS. Here we describe the spectrum of mutations occurring in familial and sporadic SVAS and attempt to define the mutational mechanisms involved in SVAS. SVAS shows variable penetrance within families but the progressive nature of the disorder in some cases, makes identification of the molecular lesions important for future preventative treatments.

MYOTONIC Received 2 December 1991; accepted 7 January 1992. dystrophy is the commonest adult form of muscular dystrophy, with an estimated incidence of 1 per 7,500, although this is likely to be an underestimate because of the difficulty of detecting minimally affected individuals. It is a multisystem autosomal dominant disorder of unknown biochemical basis 1 . No case of new mutation has been proven. We have isolated a human genomic clone that detects novel restriction fragments specific to individuals with myotonic dystrophy. A two-allele Eco Rl polymorphism is seen in normal individuals, but in most affected individuals one of the normal alleles is replaced by a larger fragment, which varies in length both between unrelated affected individuals and within families. The unstable nature of this region may explain the characteristic variation in severity and age at onset of the disease. A second polymorphism at this locus is in almost complete linkage disequilibrium with myotonic dystrophy, strongly supporting our earlier results which indicated that most cases are descended from one original mutation 2 .

FLNA gene on Xq28 encodes Filamin A protein. Mutation in FLNA causes a wide variety of disease including skeletal dysplasia, neuronal migration abnormality, cardiovascular malformation, intellectual disability and intestinal obstruction. Recently childhood onset chronic respiratory disease associated with a range of FLNA mutations has been recognised and reported.In this poster, we present two further cases of pathogenic FLNA mutation associated pulmonary disease with a focus on the importance of radiology in helping to diagnose this condition and review the literature available on the topic. Previously reported cases showed that patients with FLNA mutation display characteristic findings on chest radiograph, CT thorax and MRI brain; findings that were consistent with the cases we present here.We will present the clinical history, imaging and genetics of these infants and highlight the radiological findings that contributed to the diagnosis of FLNA mutation including diffuse ground glass opacification and persistent interstitial changes on Chest Radiographs and CT as well as periventricular heterotopia on MRI Brain.

A patient was referred in consequence of an abnormal microarray finding. The background history was of Left Congenital Diaphragmatic hernia, coarctation of Aorta and PDA. Examined at 5 weeks by Consultant Clinical Geneticist, she was non-dysmorphic, her head circumference was on 25th percentile. Neurological examination was age appropriate.ACGH showed a mosaic chromosomal imbalance involving chromosome 2q in the form of a ∼46.7Mb gain of 2q26.1–q31.2 and a ∼17.6Mb loss of 2q36.2–qter, which was estimated to be present in approximate 50% of cells. In contrast G-band karyotype analysis of phytohaemoglutinin stimulated and cultured cells showed no evidence of the abnormal cell line, with only apparently normal female 46, XX metaphases seen. So, there was a data mismatch.Parental karyotypes were both normal. Due to the peripheral blood karyotype result a skin biopsy was taken for culture and karyotyping, together with a buccal smear for FISH analysis. In addition, a second peripheral blood sample was taken to allow FISH analysis on non-cultured cells. These FISH analyses indicated the presence of an abnormal cell line in 19% (buccal smear) and 35% (whole blood) of the 200 cells analysed. Conversely cultured fibroblasts only resulted in cells with a normal female karyotype. Hence, these results indicate that the level of mosaicism varies dramatically between different cell lineages.The absence of the abnormal cell line in the cultured cells would support that this cell line is not present in the T-lymphocytes. A FBC and film showed normal white cell counts and morphology. The findings with the cultured fibroblasts may be reflective of either the absence or scarcity of the abnormal cell line in the biopsy.This most unusual case illustrates that the understanding of how test results are generated and potential limitations of each test is crucial when considering the clinical features of the patient. Further it demonstrates how mosaicism may be unequally distributed between cell types or indeed absent in the actual cell type that is being tested. It is reassuring that the patient is neurologically age appropriate. The management with clinical and developmental observation are warranted to monitor her progress.

The Allan–Herndon–Dudley syndrome (AHDS; MIM 300523) of X-linked mental retardation and hypotonia is caused by mutations in a thyroid hormone transporter gene—the monocarboxylate transporter 8 ( MCT8 also known as SLC16A2 ) gene. A 23-month-old boy with severe developmental delay, hypotonia, recurrent emesis, and irritability is described. He was diagnosed with hypothyroidism at the age of 4 months. However, T3 level was elevated. Molecular analysis of the MCT8 gene detected a single base duplication in exon 5 c.1614dupC (p.Ile539fs), consistent with a diagnosis of AHDS. While T3 is the best marker for this disorder, elevations in TSH should alert to the diagnosis.

This study shows an association between a broad range of phenotypes and either deletion or duplication of a genomic segment at chromosome 1q21.1, suggesting a fundamental role of the deletion or duplication in early development and challenging the notion that a specific mutation disposes toward a specific disorder or syndrome. This study shows an association between a broad range of phenotypes and either deletion or duplication of a genomic segment at chromosome 1q21.1, suggesting a fundamental role of the deletion or duplication in early development. Recent advances in technologies such as comparative genomic hybridization (CGH; see Glossary) allow for the routine detection of submicroscopic deletions and duplications. Several studies of persons with mental retardation or congenital anomalies of unknown cause have led to the identification of new genomic disorders. 1 – 10 Classically, criteria that have been applied to determine whether a given rearrangement is causative include de novo appearance of the deletion or duplication in an affected individual (i.e., it is not present in unaffected parents), recurrence of the same or an overlapping event in similarly affected persons, and absence of the deletion or duplication in . . .

The Old Copper Complex (OCC) refers to the production of heavy copper-tool technology by Archaic Native American societies in the Lake Superior region. To better define the timing of the OCC, we evaluated 53 (eight new and 45 published) radiocarbon (14C) dates associated with copper artifacts and mines. We compared these dates to six lake sediment-based chronologies of copper mining and annealing in the Michigan Copper District. 14C dates grouped by archaeological context show that cremation remains, and wood and cordage embedded in copper artifacts have ages that overlap with the timing of high lead (Pb) concentrations in lake sediment. In contrast, dates in stratigraphic association and from mines are younger than those from embedded and cremation materials, suggesting that the former groups reflect the timing of processes that occurred post-abandonment. The comparatively young dates obtained from copper mines therefore likely reflect abandonment and infill of the mines rather than active use. Excluding three anomalously young samples, the ages of embedded organic material associated with 15 OCC copper artifacts range from 8500 to 3580 cal BP, confirming that the OCC is among the oldest known metalworking societies in the world.