title: Four patients with speech delay, seizures and variable corpus callosum thickness sharing a 0.440 Mb deletion in region 1q44 containing the HNRPU gene.
abstract: Structural genome aberrations are frequently associated with highly variable congenital phenotypes involving mental retardation and developmental delay. Although some of these aberrations may result in recognizable phenotypes, a high degree of phenotypic variability often complicates a comprehensive clinical and genetic diagnosis. We describe four patients with overlapping deletions in chromosomal region 1q44, who show developmental delay, in particular of expressive speech, seizures, hypotonia, CNS anomalies, including variable thickness of the abnormal corpus callosum in three of them. High resolution oligonucleotide and SNP array-based segmental aneuploidy profiling showed that these three patients share a 0.440 Mb interstitial deletion, which does not overlap with previously published consensus regions of 1q44 deletions. Two copies of AKT3 and ZNF238, two previously proposed dosage sensitive candidate genes for microcephaly and agenesis of the corpus callosum, were retained in two of our patients. The deletion shared by our patients encompassed the FAM36A, HNRPU, EFCAB2 and KIF26B genes. Since HNRPU is involved in the regulation of embryonic brain development, this represents a novel plausible candidate gene for the combination of developmental delay, speech delay, hypotonia, hypo- or agenesis of the corpus callosum, and seizures in patients with 1q44 deletions. Since only one of the two patients with deletions including the ZNF124 gene showed a vermis hypoplasia, mere hemizygosity for this gene is not sufficient to cause this anomaly. Moreover, to reconcile the variability in the corpus callosum thickness, additional mechanisms, such as unmasking of hemizygous mutations, position effects and possible interactions with other loci need consideration.
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel, Christian-Albrechts University, Kiel, Germany.
authors.forename: Almuth
authors.initials: A
authors.lastname: Caliebe
authors.forename: Hester Y
authors.initials: HY
authors.lastname: Kroes
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: van der Smagt
authors.forename: José I
authors.initials: JI
authors.lastname: Martin-Subero
authors.forename: Holger
authors.initials: H
authors.lastname: Tönnies
authors.forename: Ruben
authors.initials: R
authors.lastname: van 't Slot
authors.forename: Rutger A J
authors.initials: RA
authors.lastname: Nievelstein
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Muhle
authors.forename: Ulrich
authors.initials: U
authors.lastname: Stephani
authors.forename: Karsten
authors.initials: K
authors.lastname: Alfke
authors.forename: Irina
authors.initials: I
authors.lastname: Stefanova
authors.forename: Yorck
authors.initials: Y
authors.lastname: Hellenbroich
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Ron
authors.initials: R
authors.lastname: Hochstenbach
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Martin
authors.initials: M
authors.lastname: Poot
mesh_terms: D061085:Agenesis of Corpus Callosum; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003337:Corpus Callosum / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D034722:Heterogeneous-Nuclear Ribonucleoprotein U / Q000235:genetics*; D006801:Humans; D007223:Infant; D007805:Language Development Disorders / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012640:Seizures / Q000235:genetics*
chemical_list: D015415:Biomarkers; D034722:Heterogeneous-Nuclear Ribonucleoprotein U