G2Cdb::Human Disease report

Disease id
D00000218
Name
Hydrocephalus-stenosis of the aqueduct of Sylvius
Nervous system disease
yes

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001881 L1CAM
L1 cell adhesion molecule
Y (7562969) Unknown (?) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (8401593) Duplication (Du) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9744477) Microinsertion (MI) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9744477) Nonsense (No) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9744477) Deletion (D) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (9744477) Splice site mutation (SpS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (17318848) Microdeletion (MD) Y

References

  • Contiguous gene deletion involving L1CAM and AVPR2 causes X-linked hydrocephalus with nephrogenic diabetes insipidus.

    Tegay DH, Lane AH, Roohi J and Hatchwell E

    Stony Brook University Hospital, Stony Brook, New York, USA. david.tegay@stonybrook.edu

    X-linked hydrocephalus with aqueductal stenosis (HSAS) is caused by mutation or deletion of the L1 cell adhesion molecule gene (L1CAM) at Xq28. Central diabetes insipidus (CDI) can arise as a consequence of resultant hypothalamic dysfunction from hydrocephalus and must be distinguished from nephrogenic diabetes insipidus (NDI) by exogenous vasopressin response. Causes of NDI are heterogeneous and include mutation or deletion of the arginine vasopressin receptor 2 gene (AVPR2), which is located approximately 29 kb telomeric to L1CAM. We identified a patient with both HSAS and NDI where DNA sequencing failure suggested the possibility of a contiguous gene deletion. A 32.7 kb deletion mapping from L1CAM intron1 to AVPR2 exon2 was confirmed. A 90 bp junctional insertion fragment sharing short direct repeat homology with flanking sequences was identified. To our knowledge this is the first reported case of an Xq28 microdeletion involving both L1CAM and AVPR2, defining a new contiguous gene syndrome comprised of HSAS and NDI. Contiguous gene deletion should be considered as a mechanism for all patients presenting with hydrocephalus and NDI.

    Funded by: NIGMS NIH HHS: T32 GM008444

    American journal of medical genetics. Part A 2007;143A;6;594-8

  • Identification of novel L1CAM mutations using fluorescence-assisted mismatch analysis.

    Saugier-Veber P, Martin C, Le Meur N, Lyonnet S, Munnich A, David A, Hénocq A, Héron D, Jonveaux P, Odent S, Manouvrier S, Moncla A, Morichon N, Philip N, Satge D, Tosi M and Frébourg T

    Laboratoire de Génétique Moléculaire, CHU de Rouen, France.

    The L1CAM gene, which is located in Xq28 and codes for a neuronal cell adhesion molecule, is involved in three distinct conditions: HSAS (hydrocephalus-stenosis of the aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, adductus thumbs), and SPG1 (spastic paraplegia). Molecular analysis of the L1CAM gene is labor-intensive because of the size of the coding region, which is fragmented in numerous exons, and because of the great allelic heterogeneity and distribution of the mutations. The FAMA (fluorescent assisted mismatch analysis) method combines the excellent sensitivity of the chemical cleavage method for scanning PCR fragments larger than 1 kb and the power of automated DNA sequencers. In order to optimize this method for L1CAM, we divided the gene into nine genomic fragments, each including three to four exons. These fragments were PCR-amplified using nine sets of primers containing additional rare universal sequences. A second-stage PCR, per formed with the two dye-labeled universal primers, allowed us to generate 1-kb-labeled fragments, which were then submitted to the chemical cleavage analysis. Among 12 French families with HSAS and/or MASA, we identified nine distinct L1CAM mutations, seven of which were novel, and an intronic variation. This study demonstrates that FAMA allows rapid and reliable detection of mutations in the L1CAM gene and thus represents one of the most appropriate methods to provide diagnosis for accurate genetic counseling in families with HSAS, MASA, or SPG1.

    Human mutation 1998;12;4;259-66

  • Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS.

    Ruiz JC, Cuppens H, Legius E, Fryns JP, Glover T, Marynen P and Cassiman JJ

    Centre for Human Genetics, University of Leuven, Belgium.

    The suggestion that the three X linked syndromes X linked spastic paraplegia (MIM 312900), MASA syndrome (MIM 303350), and X linked hydrocephalus owing to stenosis of the aqueduct of Sylvius (MIM 307000) are variable clinical manifestations of mutations at the same locus at Xq28 was confirmed by the finding of mutations in the L1-CAM gene in the three syndromes. Recently, two families in which different subjects showed a clearly different phenotype within the same family of the three X linked syndromes were described. A reverse transcription PCR assay was developed for the analysis of the L1-CAM cDNA in two of the members of these families. RNA isolated from EBV transformed cell lines and a colon carcinoma derived cell line was used as a starting material. The L1-CAM cDNA of two male patients from each family was sequenced. We report two new mutations in the L1-CAM gene in these two families showing that the three different phenotypes observed in different generations within the same family are variable phenotypic expressions of the same mutation.

    Journal of medical genetics 1995;32;7;549-52

  • A duplication in the L1CAM gene associated with X-linked hydrocephalus.

    Van Camp G, Vits L, Coucke P, Lyonnet S, Schrander-Stumpel C, Darby J, Holden J, Munnich A and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Recently, a mutation in the gene for the neural cell adhesion molecule L1CAM, located at chromosome Xq28, was found in a family with X-linked hydrocephalus (HSAS). However, as the L1CAM mutation could only be identified in one HSAS family, it remained unclear whether or not L1CAM was the gene responsible for HSAS. We have conducted a mutation analysis of L1CAM in 25 HSAS families. The mutation reported previously was not found in any of these families. In one family, however, a 1.3 kilobases (kb) genomic duplication was identified, cosegregating with HSAS and significantly changing the intracellular domain of the L1CAM protein. These results confirm that L1CAM is the HSAS gene.

    Nature genetics 1993;4;4;421-5

Literature (4)

Pubmed - human_disease

  • Contiguous gene deletion involving L1CAM and AVPR2 causes X-linked hydrocephalus with nephrogenic diabetes insipidus.

    Tegay DH, Lane AH, Roohi J and Hatchwell E

    Stony Brook University Hospital, Stony Brook, New York, USA. david.tegay@stonybrook.edu

    X-linked hydrocephalus with aqueductal stenosis (HSAS) is caused by mutation or deletion of the L1 cell adhesion molecule gene (L1CAM) at Xq28. Central diabetes insipidus (CDI) can arise as a consequence of resultant hypothalamic dysfunction from hydrocephalus and must be distinguished from nephrogenic diabetes insipidus (NDI) by exogenous vasopressin response. Causes of NDI are heterogeneous and include mutation or deletion of the arginine vasopressin receptor 2 gene (AVPR2), which is located approximately 29 kb telomeric to L1CAM. We identified a patient with both HSAS and NDI where DNA sequencing failure suggested the possibility of a contiguous gene deletion. A 32.7 kb deletion mapping from L1CAM intron1 to AVPR2 exon2 was confirmed. A 90 bp junctional insertion fragment sharing short direct repeat homology with flanking sequences was identified. To our knowledge this is the first reported case of an Xq28 microdeletion involving both L1CAM and AVPR2, defining a new contiguous gene syndrome comprised of HSAS and NDI. Contiguous gene deletion should be considered as a mechanism for all patients presenting with hydrocephalus and NDI.

    Funded by: NIGMS NIH HHS: T32 GM008444

    American journal of medical genetics. Part A 2007;143A;6;594-8

  • A duplication in the L1CAM gene associated with X-linked hydrocephalus.

    Van Camp G, Vits L, Coucke P, Lyonnet S, Schrander-Stumpel C, Darby J, Holden J, Munnich A and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Recently, a mutation in the gene for the neural cell adhesion molecule L1CAM, located at chromosome Xq28, was found in a family with X-linked hydrocephalus (HSAS). However, as the L1CAM mutation could only be identified in one HSAS family, it remained unclear whether or not L1CAM was the gene responsible for HSAS. We have conducted a mutation analysis of L1CAM in 25 HSAS families. The mutation reported previously was not found in any of these families. In one family, however, a 1.3 kilobases (kb) genomic duplication was identified, cosegregating with HSAS and significantly changing the intracellular domain of the L1CAM protein. These results confirm that L1CAM is the HSAS gene.

    Nature genetics 1993;4;4;421-5

Pubmed - other

  • Identification of novel L1CAM mutations using fluorescence-assisted mismatch analysis.

    Saugier-Veber P, Martin C, Le Meur N, Lyonnet S, Munnich A, David A, Hénocq A, Héron D, Jonveaux P, Odent S, Manouvrier S, Moncla A, Morichon N, Philip N, Satge D, Tosi M and Frébourg T

    Laboratoire de Génétique Moléculaire, CHU de Rouen, France.

    The L1CAM gene, which is located in Xq28 and codes for a neuronal cell adhesion molecule, is involved in three distinct conditions: HSAS (hydrocephalus-stenosis of the aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, adductus thumbs), and SPG1 (spastic paraplegia). Molecular analysis of the L1CAM gene is labor-intensive because of the size of the coding region, which is fragmented in numerous exons, and because of the great allelic heterogeneity and distribution of the mutations. The FAMA (fluorescent assisted mismatch analysis) method combines the excellent sensitivity of the chemical cleavage method for scanning PCR fragments larger than 1 kb and the power of automated DNA sequencers. In order to optimize this method for L1CAM, we divided the gene into nine genomic fragments, each including three to four exons. These fragments were PCR-amplified using nine sets of primers containing additional rare universal sequences. A second-stage PCR, per formed with the two dye-labeled universal primers, allowed us to generate 1-kb-labeled fragments, which were then submitted to the chemical cleavage analysis. Among 12 French families with HSAS and/or MASA, we identified nine distinct L1CAM mutations, seven of which were novel, and an intronic variation. This study demonstrates that FAMA allows rapid and reliable detection of mutations in the L1CAM gene and thus represents one of the most appropriate methods to provide diagnosis for accurate genetic counseling in families with HSAS, MASA, or SPG1.

    Human mutation 1998;12;4;259-66

  • Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS.

    Ruiz JC, Cuppens H, Legius E, Fryns JP, Glover T, Marynen P and Cassiman JJ

    Centre for Human Genetics, University of Leuven, Belgium.

    The suggestion that the three X linked syndromes X linked spastic paraplegia (MIM 312900), MASA syndrome (MIM 303350), and X linked hydrocephalus owing to stenosis of the aqueduct of Sylvius (MIM 307000) are variable clinical manifestations of mutations at the same locus at Xq28 was confirmed by the finding of mutations in the L1-CAM gene in the three syndromes. Recently, two families in which different subjects showed a clearly different phenotype within the same family of the three X linked syndromes were described. A reverse transcription PCR assay was developed for the analysis of the L1-CAM cDNA in two of the members of these families. RNA isolated from EBV transformed cell lines and a colon carcinoma derived cell line was used as a starting material. The L1-CAM cDNA of two male patients from each family was sequenced. We report two new mutations in the L1-CAM gene in these two families showing that the three different phenotypes observed in different generations within the same family are variable phenotypic expressions of the same mutation.

    Journal of medical genetics 1995;32;7;549-52

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EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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