C. Hansen

Truncation of the Down Syndrome Candidate Gene DYRK1A in Two Unrelated Patients with Microcephaly

We have identified and characterized two unrelated patients with prenatal onset of microcephaly, intrauterine growth retardation, feeding problems, developmental delay, and febrile seizures/epilepsy who both carry a de novo balanced translocation that truncates the DYRK1A gene at chromosome 21q22.2. DYRK1A belongs to the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family, which is highly conserved throughout evolution. Given its localization in both the Down syndrome critical region and in the minimal region for partial monosomy 21, the gene has been studied intensively in animals and in humans, and DYRK1A has been proposed to be involved in the neurodevelopmental alterations associated with these syndromes. In the present study, we show that truncating mutations of DYRK1A result in a clinical phenotype including microcephaly.

Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B

Halgren C, Kjaergaard S, Bak M, Hansen C, El‐Schich Z, Anderson CM, Henriksen KF, Hjalgrim H, Kirchhoff M, Bijlsma EK, Nielsen M, den Hollander NS, Ruivenkamp CAL, Isidor B, Le Caignec C, Zannolli R, Mucciolo M, Renieri A, Mari F, Anderlid B‐M, Andrieux J, Dieux A, Tommerup N, Bache I. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B.

The human hedgehog-interacting protein gene: Structure and chromosome mapping to 4q31.21→q31.3

Hedgehog-interacting protein (Hhip) is a novel regulatory component in the vertebrate hedgehog-signalling pathway. The murine Hhip encodes a type I TM protein that attenuates hedgehog signalling by binding all three mammalian hedgehog proteins. Here we describe the cloning and characterisation of the homologous human hedgehog-interacting protein gene (HHIP). HHIP comprises 13 exons and spans >91kb encoding a protein of 700 aa which shares 94% sequence iden- tity with mouse Hhip. HHIP maps to chromosome 4q31.21→ q31.3. Additionally, we have mapped murine Hhip to chromosome 8.

Interstitial deletion of chromosome 4p associated with mild mental retardation, epilepsy and polymicrogyria of the left temporal lobe

In this study, we present a 38‐year‐old woman with an interstitial deletion of 4p15.1‐15.3, mild mental retardation, epilepsy and polymicrogyria adjacent to an arachnoid cyst of the left temporal lobe. The deletion was ascertained through array‐comparative genome hybridization screening of patients with epilepsy and brain malformations. To date, about 35 patients with cytogenetically visible deletions involving 4p15 and without Wolf‐Hirschhorn syndrome have been described, but the extent of the deletions has not been determined in the majority of these cases. The clinical manifestations of the patient described in this study were similar but not identical to the previously reported cases with 4p15 interstitial deletions. This finding indicates the presence of one or more genes involved in brain development and epilepsy in this chromosome region.

Clinical features and molecular genetic analysis of a boy with Prader‐Willi syndrome caused by an imprinting defect

Abstract Prader‐Willi syndrome (PWS) is a neuroendocrine disorder caused by a non‐functioning paternally derived gene(s) within the chromosome region 15q11‐q13. Most cases result from microscopically visible deletions of paternal origin, or maternal uniparental disomy of chromosome 15. In both instances no recurrence has been reported. In rare cases, PWS is associated with lack of gene expression from the paternal allele due to an imprinting defect. We report the clinical features and the molecular genetic analysis of the first Danish child with PWS due to a defect of the putative imprinting centre (IC). When the imprinting mutation is inherited from a carrier father, the risk that future children will be affected is theoretically 50%. It is therefore important that these families are referred to a geneticist for counselling and further investigation. Prenatal diagnosis is currently only feasible when the mutation has been identified in the affected child.

Balanced translocation in a patient with severe myoclonic epilepsy of infancy disrupts the sodium channel gene SCN1A.

In a patient with severe myoclonic epilepsy of infancy (SMEI), we identified a de novo balanced translocation, t(2;5)(q24.3,q34). The breakpoint on chromosome 2q24.3 truncated the SCN1A gene and the 5q34 breakpoint was within a highly conserved genomic region. Point mutations or microdeletions of SCN1A have previously been identified in SMEI patients, but this is the first report of a balanced translocation disrupting the SCN1A gene in an epilepsy patient. We therefore recommend that SMEI patients without SCN1A microdeletions or point mutations should be investigated for chromosomal rearrangements.

Assignment1 of the human zinc finger gene, ZNF288, to chromosome 3 band q13.2 by radiation hybrid mapping and fluorescence in situ hybridisation

Zinc finger genes comprise a large family of genes, which have been associated with normal and abnormal development, including development of extremities, regulation of neuronal gene expression (Theil et al., 1999), motor neuron development and migration (Baum et al., 1999), and abnormal brain development (Karlstrom et al., 1999). Zinc finger genes have also been associated with cancer (Stein et al., 1999) and systemic lupus erythematosus (Tsao et al., 1999). The human zinc finger gene, ZNF288, has high homology to a novel murine POZ/zinc finger transcription factor encoding gene, Oda-8, which is expressed in developing neurons during mouse brain development (Kjaerulf et al., unpublished, accession number AL050276). Although the function of ZNF288 remains to be elucidated, it is tempting to speculate that ZNF288 codes for a protein that may be involved in brain development. Here we report the assignment of the human ZNF288 gene to human chromosome 3q13.2 by radiation hybrid mapping and fluorescence in situ hybridisation (FISH). Materials and methods