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1.
Hum Mutat ; 31(11): E1851-60, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20848658

ABSTRACT

Mental retardation affects 2-3% of the population and shows a high heritability.Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors.We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language.


Subject(s)
Forkhead Transcription Factors/genetics , Intellectual Disability/genetics , Language Disorders/genetics , Repressor Proteins/genetics , Sequence Deletion , Speech Disorders/genetics , Base Sequence , Case-Control Studies , Child , Child, Preschool , Chromosomes, Artificial, Bacterial/genetics , DNA Breaks , DNA Primers/genetics , Female , Heterozygote , Humans , In Situ Hybridization, Fluorescence , Male , Polymerase Chain Reaction
2.
Am J Med Genet A ; 149A(10): 2106-12, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19676056

ABSTRACT

The pericentromeric region on 16p appears to be susceptible to chromosomal rearrangements and several patients with rearrangements in this region have been described. We report on a further patient with a microdeletion 16p11.2-p12.2 in the context of described patients with a deletion in the pericentromeric region of 16p. Minor facial anomalies, feeding difficulties, significant delay in speech development, and recurrent ear infections are common symptoms of the microdeletion syndrome 16p11.2-p12.2. All reported patients so far share a common distal breakpoint at 16p12.2 but vary in the proximal breakpoint at 16p11.2. The microdeletion 16p11.2-p12.2 should be distinguished from the approximately 500 kb microdeletion in 16p11.2 which seems to be associated with autism but not with facial manifestations, feeding difficulties, or developmental delay.


Subject(s)
Abnormalities, Multiple/genetics , Chromosome Deletion , Chromosomes, Human, Pair 16 , Language Development Disorders/genetics , Otitis/genetics , Adolescent , Follow-Up Studies , Humans , Male , Otitis/complications , Syndrome
4.
Am J Hum Genet ; 81(4): 768-79, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17847001

ABSTRACT

Whole-genome analysis using high-density single-nucleotide-polymorphism oligonucleotide arrays allows identification of microdeletions, microduplications, and uniparental disomies. We studied 67 children with unexplained mental retardation with normal karyotypes, as assessed by G-banded chromosome analyses. Their DNAs were analyzed with Affymetrix 100K arrays. We detected 11 copy-number variations that most likely are causative of mental retardation, because they either arose de novo (9 cases) and/or overlapped with known microdeletions (2 cases). The eight deletions and three duplications varied in size from 200 kb to 7.5 Mb. Of the 11 copy-number variations, 5 were flanked by low-copy repeats. Two of those, on chromosomes 15q25.2 and Xp22.31, have not been described before and have a high probability of being causative of new deletion and duplication syndromes, respectively. In one patient, we found a deletion affecting only a single gene, MBD5, which codes for the methyl-CpG-binding domain protein 5. In addition to the 67 children, we investigated 4 mentally retarded children with apparent balanced translocations and detected four deletions at breakpoint regions ranging in size from 1.1 to 14 Mb.


Subject(s)
Gene Dosage , Genetic Variation , Intellectual Disability/genetics , Polymorphism, Single Nucleotide , Base Sequence , Child , Child, Preschool , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/pathology , DNA Primers/genetics , Female , Gene Deletion , Gene Duplication , Humans , Infant , Intellectual Disability/pathology , Male , Molecular Sequence Data , Oligonucleotide Array Sequence Analysis , Phenotype , Syndrome , Translocation, Genetic
5.
Brain ; 130(Pt 10): 2736-45, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17898012

ABSTRACT

Myoclonus-dystonia (M-D, DYT11) is a dystonia plus syndrome characterized by brief myoclonic jerks predominantly of neck and upper limbs in combination with focal or segmental dystonia. It is caused by heterozygous mutations of the epsilon-sarcoglycan (SGCE) gene on chromosome 7q21.3. We present three patients with heterozygous large deletions in the 7q21.13-21.3 region. By quantitative analysis of single nucleotide polymorphism (SNP) oligonucleotide arrays, the deletion size was determined to range from 1.63 to 8.78 Mb. All deletions contained the maternally imprinted SGCE gene and up to 43 additional neighbouring genes. Two of the patients presented with typical M-D, whereas one paediatric patient with split-hand/split-foot malformation and sensorineural hearing loss (SHFM1D, OMIM 220600) had not developed M-D at the age of 9 years. This patient had the largest deletion of 8.78 Mb (7q21.13-21.3) containing also SHFM1, DLX6 and DLX5, which had been previously shown to be deleted in SHFM1D. In two patients, the deletions removed the paternal allele of the KRIT1 gene, which is a major cause of cavernous cerebral malformations type 1 (CCM1). Only the adult patient showed asymptomatic cavernous cerebral malformations on cranial MRI, underlining age-dependent penetrance and haploinsufficiency as pivotal features of patients with KRIT1 mutations. All three deletions contained the COL1A2 gene. In contrast to dominant negative point mutations, which cause osteogenesis imperfecta with bone fractures, haploinsufficiency of COL1A2 resulted only in subtle symptoms like recurrent joint subluxation or hypodontia. Assessing copy number variations by SNP arrays is an easy and reliable technique to delineate the size of human interstitial deletions. It will therefore become a standard technique to study patients, in whom heterozygous whole gene deletions are detected and information on neighbouring deleted genes is required for comprehensive genetic counselling and clinical management.


Subject(s)
Chromosomes, Human, Pair 7/genetics , Dystonic Disorders/genetics , Gene Deletion , Myoclonus/genetics , Sarcoglycans/genetics , Child , Child, Preschool , DNA Mutational Analysis/methods , Dystonic Disorders/diagnosis , Female , Genotype , Glycosylation , Heterozygote , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Myoclonus/diagnosis , Phenotype , Polymerase Chain Reaction/methods , Polymorphism, Single Nucleotide , Syndrome
6.
Nat Genet ; 38(11): 1248-50, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17033625

ABSTRACT

Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.


Subject(s)
Bone Matrix/metabolism , Extracellular Matrix Proteins/genetics , Hypophosphatemia/genetics , Phosphates/metabolism , Phosphoproteins/genetics , Adolescent , Adult , Child , Extracellular Matrix Proteins/metabolism , Extracellular Matrix Proteins/physiology , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Homeostasis , Humans , Infant , Mutation , PHEX Phosphate Regulating Neutral Endopeptidase/genetics , PHEX Phosphate Regulating Neutral Endopeptidase/metabolism , Pedigree , Phosphoproteins/metabolism , Phosphoproteins/physiology
7.
Hum Mutat ; 27(7): 633-9, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16752389

ABSTRACT

In two large Turkish consanguineous families, a locus for autosomal recessive nonsyndromic hearing loss (ARNSHL) was mapped to chromosome 6p21.3 by genome-wide linkage analysis in an interval overlapping with the loci DFNB53 (COL11A2), DFNB66, and DFNB67. Fine mapping excluded DFNB53 and subsequently homozygous mutations were identified in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also named tetraspan membrane protein of hair cell stereocilia (TMHS) gene, which was recently shown to be mutated in the "hurry scurry" mouse and in two DFNB67-linked families from Pakistan. In one family, we found a homozygous one-base pair deletion, c.649delG (p.Glu216ArgfsX26) and in the other family we identified a homozygous transition c.494C>T (p.Thr165Met). Further screening of index patients from 96 Turkish ARNSHL families and 90 Dutch ARNSHL patients identified one additional Turkish family carrying the c.649delG mutation. Haplotype analysis revealed that the c.649delG mutation was located on a common haplotype in both families. Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea.


Subject(s)
Frameshift Mutation , Hearing Loss, Bilateral/genetics , Hearing Loss, Sensorineural/genetics , Membrane Proteins/genetics , Mutation, Missense , Amino Acid Sequence , Chromosome Mapping , Chromosomes, Human, Pair 5 , Consanguinity , DNA Mutational Analysis , Female , Genetic Linkage , Haplotypes , Hearing Loss, Bilateral/diagnosis , Hearing Loss, Sensorineural/diagnosis , Humans , Male , Molecular Sequence Data , Pedigree , Sequence Alignment
8.
Am J Med Genet A ; 140(7): 764-8, 2006 Apr 01.
Article in English | MEDLINE | ID: mdl-16523518

ABSTRACT

In recent years, the spectrum of available methods for the characterization of chromosomal aberrations has significantly increased. Micro-array technologies now allow the rapid fine mapping of small genomic imbalances. Here we used various technologies to characterize a de novo translocation t(2;15) in a girl with dysmorphic features, severe developmental delay and frequent seizures. Multiplex-FISH (M-FISH) excluded the involvement of other chromosomes than chromosomes 2 and 15. We used an oligonucleotide array containing more than 10.000 SNPs, that is, the GeneChip Mapping 10K 2.0 SNP Affymetrix array, and readily fine-mapped a deletion in chromosomal region 2q24.1 --> 2q31.1. The extent of this deletion was verified with multicolor BAC-clone hybridizations. The deletion has a size of about 13 Mb and is within a gene rich region containing about 76 genes. Interestingly, several of these genes are ion channel genes or genes involved in neuron differentiation, so that the frequently occurring seizures are probably due to loss or haploinsufficiency of one or more of these genes.


Subject(s)
Abnormalities, Multiple/genetics , Chromosome Deletion , Chromosomes, Human, Pair 2/genetics , Ear/abnormalities , Epilepsy/pathology , Abnormalities, Multiple/pathology , Child, Preschool , Chromosome Banding , Fatal Outcome , Female , Genome, Human , Humans , Karyotyping , Nucleic Acid Hybridization/methods
9.
Am J Hum Genet ; 78(2): 193-201, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16358215

ABSTRACT

Hypophosphatemia due to isolated renal phosphate wasting results from a heterogeneous group of disorders. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form that is characterized by reduced renal phosphate reabsorption, hypophosphatemia, and rickets. It can be distinguished from other forms of hypophosphatemia by increased serum levels of 1,25-dihydroxyvitamin D resulting in hypercalciuria. Using SNP array genotyping, we mapped the disease locus in two consanguineous families to the end of the long arm of chromosome 9. The candidate region contained a sodium-phosphate cotransporter gene, SLC34A3, which has been shown to be expressed in proximal tubulus cells. Sequencing of this gene revealed disease-associated mutations in five families, including two frameshift and one splice-site mutation. Loss of function of the SLC34A3 protein presumably results in a primary renal tubular defect and is compatible with the HHRH phenotype. We also show that the phosphaturic factor FGF23 (fibroblast growth factor 23), which is increased in X-linked hypophosphatemic rickets and carries activating mutations in autosomal dominant hypophosphatemic rickets, is at normal or low-normal serum levels in the patients with HHRH, further supporting a primary renal defect. Identification of the gene mutated in a further form of hypophosphatemia adds to the understanding of phosphate homeostasis and may help to elucidate the interaction of the proteins involved in this pathway.


Subject(s)
Chromosomes, Human, Pair 9/genetics , Familial Hypophosphatemic Rickets/genetics , Genetic Diseases, X-Linked , Hypercalciuria/genetics , Sodium-Phosphate Cotransporter Proteins, Type IIc/genetics , Animals , Child , Child, Preschool , Chromosome Mapping , DNA Mutational Analysis , Familial Hypophosphatemic Rickets/classification , Familial Hypophosphatemic Rickets/metabolism , Female , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/blood , Genetic Linkage , Humans , Kidney Tubules, Proximal/metabolism , Male , Mice , Mutation , Pedigree , Phylogeny , Polymorphism, Single Nucleotide
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