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Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly

18 Apr, 14 | by hqqu

Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly. We collected the largest sample to date of individuals with variants affecting GLI2 and characterized their phenotype. This included previously published cases as well as new unpublished individuals. We found that individuals with mutations resulting in loss of function rather (versus those with variants of unknown significance) typically had a narrow phenotype including polydactyly and pituitary anomalies as well as subtle facial features, as opposed to frank HPE. (By Kelly Bear, http://jmg.bmj.com/content/early/2014/04/17/jmedgenet-2013-102249 )

A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma

15 Apr, 14 | by hqqu

Retinitis pigmentosa is a group of genetically inherited eye diseases which represents the most frequent cause of inherited blindness worldwide. Persons with retinitis pigmentosa experience night blindness, which is followed by tunnel vision due to the progressive degeneration of the light sensing cells called rods and cones. Approximately 60 different genes can be defective in retinitis pigmentosa. By sequence analysis of all 20.000 human genes, we could identify defects in DHX38 in 4 retinitis pigmentosa patients of a consanguineous Pakistani family. DHX38 encodes a protein that is important for the processing of RNA molecules, which are crucial intermediates between DNA and protein molecules. This finding enables genetic counseling in this family and provides new insights into the disease mechanism. (By Prof. dr. Frans P.M. Cremers, http://jmg.bmj.com/content/early/2014/04/15/jmedgenet-2014-102316 )

A familial disorder of altered DNA-methylation

10 Apr, 14 | by hqqu

Genomic imprinting is an epigenetic process leading to parent-of-origin specific DNA methylation and gene expression. There are several recognizable phenotypes caused by DNA-methylation changes at disease specific imprinted loci. In the recent years it became obvious that some patients exhibit changes of DNA-methylation at multiple imprinted loci. We report a family with three offspring who were all affected by a widespread disorder of DNA methylation not only of maternally and paternally imprinted genes but also of a considerable number of loci not known to be associated with parent-of-origin specific DNA-methylation. This family suggests the existence of a hitherto unrecognised disorder of genomic imprinting. (By Dr. med. Almuth Caliebe, http://jmg.bmj.com/content/early/2014/04/10/jmedgenet-2013-102149 )

A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups

10 Apr, 14 | by hqqu

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, affecting > 30 million children worldwide. Children usually develop AIS around the time of the adolescent growth spurt, and girls are at greater risk of severe deformity requiring treatment. Until recently the causes of AIS have remained unknown. In 2011 a genome-wide association study (GWAS) in Japanese patients identified genetic markers near the LBX1 gene as risk factors for AIS. In this new study coordinated through the International Consortium for Scoliosis Genetics (ICSG), we demonstrate that the LBX1 locus is strongly associated with AIS in multiple ethnic populations (Japanese, Chinese, and non-Hispanic white), and that it is probably relevant in boys as well as girls. LBX1 is a regulator of other genes and may participate in AIS by effects on muscle and nerve development. (By Dr. Carol Wise, http://jmg.bmj.com/content/early/2014/04/10/jmedgenet-2013-102067 )

ADAP2 in heart development: a candidate gene for the occurrence of Cardiovascular Malformations in NF1 Microdeletion Syndrome

7 Apr, 14 | by hqqu

The NF1 microdeletion syndrome is caused by the deletion of a chromosome 17 region encompassing the NF1 gene and flanking genes. We previously found that the patients with the syndrome display a significantly higher incidence of Cardiovascular Malformations (CVMs) than that observed in the NF1 patients with intragenic mutations, suggesting that genes present in the deleted segment are essential for normal heart development.

Here we showed that one of these genes, ADAP2, is expressed in heart during fundamental phases of cardiac development. The functional inactivation of ADAP2 in zebrafish demonstrated its important role in heart development and pointed to ADAP2 as the best candidate gene for the occurrence of CVMs in NF1-microdeleted patients. Our study constitutes a step towards a better comprehension of the complex phenotypic spectrum of the syndrome. (By Dr. Marco Venturin, http://jmg.bmj.com/content/early/2014/04/07/jmedgenet-2013-102240 )

Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia

4 Apr, 14 | by hqqu

Sedaghatian-type spondylometaphyseal dysplasia is a rare syndrome characterized by abnormal bone development with shortened limbs and flattened spine.  Affected children also have heart rhythm defects and brain abnormalities such that they pass away shortly after birth.  Eighteen infants affected with this rare disease have been reported worldwide.  We studied two families and identified loss-of-function mutations in the gene GPX4, a member of the glutathione peroxidase family of antioxidant defense enzymes that protects cells against cell death and lipid peroxidation.  Our findings highlight the importance of proper functioning of this enzyme in development of the cardiac, nervous and skeletal systems. (By Dr. Kym Boycott, http://jmg.bmj.com/content/early/2014/04/04/jmedgenet-2013-102218 )

RB1 mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients

1 Apr, 14 | by hqqu

Retinoblastoma is a cancer of the retina that occurs in young children, in the majority of cases initiated by mutations in the RB1 tumour suppressor gene. About 40% of retinoblastoma patients have a germline RB1 mutation which gives them a hereditary predisposition to develop retinoblastoma. Knowledge of the presence of an RB1 mutation can help in clinical care and family planning. The Dutch National Retinoblastoma Register collects information on all Rb patients diagnosed in the Netherlands. In this paper the authors describe the results of RB1 mutation scanning in 529 Dutch retinoblastoma patients from 433 independent families from the Register. We detected an RB1 mutation in 92% of familial and non-familial bilateral patients. A total of 187 RB1 germline mutations were found, including 33 novel mutations. Several three-generation families with incomplete penetrance RB1 mutations are described. (By Berber Mol, http://jmg.bmj.com/content/early/2014/03/31/jmedgenet-2014-102264 )

Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair

26 Mar, 14 | by hqqu

The combination of keratoderma (thickened palms and soles) with woolly hair should always alert the clinician to the possibility of Naxos or Carvajal syndromes. These two autosomal recessive conditions are caused by mutations in desmosomal proteins, which are critical for cellular adhesion in the skin. Since desmosomes are abundant in the cardiac muscle, these syndromes are also associated with severe heart disease that leads to sudden death at an early age. The authors studied two families with keratoderma and woolly hair without associated heart disease, and identified a mutation in KANK2, which encodes a non-desmosomal protein that controls the transcription of steroid receptor target genes. Mutation in this gene leads to excess activation of the vitamin D receptor, emphasizing its importance in normal hair and skin phenotypes. (By Dr. Yuval Ramot, http://jmg.bmj.com/content/early/2014/03/26/jmedgenet-2014-102346 )

Genome-wide association study identifies new disease loci for isolated clubfoot

25 Mar, 14 | by hqqu

Clubfoot is a common congenital birth defect that affects nearly 1 in 1000 births.  To identify genetic risk factors associated with clubfoot, we performed a genome-wide association study of 396 isolated clubfoot patients and 1000 controls of European descent.  Strongest evidence for an association of clubfoot was found with an intergenic SNP on chromosome 12q24.31 between NCOR2 and ZNF664 that was also significant on replication.  Additional suggestive SNPs were identified near FOXN3, SORCS1, and MMP7/TMEM123 that also confirmed on replication.  Our report suggests a potential role for common genetic variation in several genes that have not previously been implicated in clubfoot pathogenesis. (By Dr. Christina A Gurnett, http://jmg.bmj.com/content/early/2014/03/25/jmedgenet-2014-102303 )

Mapping of hepatic expression quantitative trait loci (eQTLs) in a Han Chinese population

24 Mar, 14 | by hqqu

Understanding genetic control for gene expression in human livers is important to elucidate the mechanism underlying health and disease. Wang et al. carried out the first genome-wide analysis in liver tissues of a Han Chinese population and observed 1,669 genetic loci significantly associated with hepatic gene expression. The study also found that at least 41% of these alleles were significantly associated hepatic gene expression in a Caucasian population. In addition, the study revealed that disease-associated alleles and the alleles significantly involved in drug metabolism and response were more likely to control gene expression in human livers. (By Dr. Zhihai Peng, http://jmg.bmj.com/content/early/2014/03/24/jmedgenet-2013-102045 )

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