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Identification of the first dominant mutation of LAMA5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix

22 Jul, 17 | by hqqu

Laminin alpha 5 gene (LAMA5) plays a master role in the extracellular matrix in all mammalian tissues; mice defective of LAMA5 do not overcome embryonic life. In this paper a previously unknown autosomal dominant clinico-pathological syndrome is described which segregates with the mutation c.9418G>A (p.V3140M) of LAMA5 in an informative Italian family.  The results of this study highlight the importance of LAMA5 in the histogenesis, developmental patterning, maintenance and repair of all body tissues and also open new perspectives to investigate on the pathogenesis of pathologies  such as, night blindness, intestinal malabsorption, osteoarthritis, altered scarring, and  new strategies for their treatment. (By Dr. Teresa Esposito, http://jmg.bmj.com/content/early/2017/07/22/jmedgenet-2017-104555 )

Assessing genome-wide copy number variation in the Han Chinese population

13 Jul, 17 | by hqqu

Copy number variation (CNV) is an important source of human genetic diversity, which contributes to Mendelian disorders as well as complex diseases. We conducted a genome-wide CNV discovery in 451 males of Han Chinese by using high-density comparative hybridization arrays. The CNVs we reported are in high quality and representative of Han Chinese from 28 dialects and diverse geographical regions. More than half of the variants are novel and have not been reported yet. These data are complementary to public sources of human genomic data, and the CNV map may facilitate in the identification of pathogenic CNVs and further biomedical studies involving the Han Chinese populations. (By Prof. Dr. Shuhua Xu, http://jmg.bmj.com/content/early/2017/07/13/jmedgenet-2017-104613 )

The focal facial dermal dysplasias: phenotypic spectrum and molecular genetic heterogeneity

29 Jun, 17 | by hqqu

Focal Facial Dermal Dysplasias (FFDDs) are four developmental genetic disorders with similar bilateral “scar-like” facial lesions at birth and are classified by the lesion location: bitemporal for the FFDD subtypes 1-3 and peri-auricular for FFDD subtype 4. This review summarizes the clinical features of the subtypes and the genetic defects underlying FFDD3 and FFDD4, while the underlying genetic defects in FFDD1 and FFDD2 remain unknown. Additionally, two autosomal dominant developmental disorders with overlapping facial lesions, Ablepharon-Macrostomia syndrome and Barber-Say syndrome, are discussed. Recognition of these disorders and further investigation of their genetic defects may provide insights into the genetic pathways of facial development. (By Brenden Chen, http://jmg.bmj.com/content/early/2017/06/29/jmedgenet-2017-104561 )

Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa

24 Jun, 17 | by hqqu

Pathogenic variants (mutations) in the Abelson helper integration site 1 (AHI1) gene are known to be associated with Joubert syndrome, a developmental disorder causing visual, cognitive and motor deficits. In this study, we show that some pathogenic variants in the AHI1 gene can cause visual impairment, without other symptoms or signs suggestive of Joubert syndrome. Such variants were located in a specific domain (WD40 domain) of the encoded protein and have only subtle effects when expressed in cells in culture. The data support the hypothesis that these “non-syndromic” variants give residual protein function, while alleles associated with Joubert syndrome completely abolish function. (By Dr. Lonneke Haer-Wigman, http://jmg.bmj.com/content/early/2017/06/24/jmedgenet-2016-104200 )

First evidence of genotype-phenotype correlations in Gorlin syndrome

8 Jun, 17 | by hqqu

Gorlin syndrome (GS) is a genetic disease that causes affected people to develop skin tumours and puts them at risk of other tumours as well as other abnormal features of skin and bone. Most cases of GS are caused by gene changes in the PTCH1 gene, while fewer cases are caused by changes in the related gene, SUFU. In other cases it is unknown what gene change is causing the disease. In our study, we have found that several features of GS may be explained by the specific type of gene change causing their disease. (By Dr. Miriam J. Smith, http://jmg.bmj.com/content/early/2017/06/08/jmedgenet-2017-104669 )

Genetic causes of optic nerve hypoplasia

13 May, 17 | by hqqu

Optic nerve hypoplasia is characterized by the underdevelopment of the optic nerves, which carry the visual information from the retina to the brain. Optic nerve hypoplasia represents the most common congenital optic nerve anomaly and a leading cause of blindness in the United States. This review highlights the growing number of genes that have been identified to cause optic nerve hypoplasia when mutated. The human clinical features associated with respective gene mutations, and the mouse models that have been generated to gain a deeper understanding of the disorders, are discussed. (By Dr. Christian Schaaf, http://jmg.bmj.com/content/early/2017/05/13/jmedgenet-2017-104626 )

The BRCA1 R1699Q intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium

10 May, 17 | by hqqu

Mutations in BRCA1 confer high life-time risks for breast cancer (BC): 68% and ovarian cancer (OC): 39%. Our paper describes the cancer risks associated with the missense mutation BRCA1*R1699Q in a large group of families ascertained internationally. Results show that the risks associated with this mutation, BC 20%  and OC 6%, are lower than for the average BRCA1 mutations. Based on these risks we proposed mutation-specific recommendations for clinical management. We also found that, as occurs with moderate risk genes, cancer risks in families with this intermediate risk mutation are likely to be influenced by additional genetic factors. (By Mrs. Setareh Moghadasi and Dr. E. Gomez Garcia, http://jmg.bmj.com/content/early/2017/05/10/jmedgenet-2017-104560 )

Female-to-male sex reversal associated with unique Xp21.2 deletion disrupting genomic regulatory architecture of the dosage-sensitive sex reversal region

8 May, 17 | by hqqu

During the early stages of embryo growth, the SRY gene located on the Y chromosome triggers male sexual development. Typically, embryos with two X chromosomes develop into females. We report a child with two X chromosomes who had male appearing genitalia (female-to-male sex reversal) due to a deletion of a small X chromosome segment controlling testis determination. Our study shows how gene dosage and disrupted gene regulation can switch gonadal development to activate male differentiation in the absence of the Y chromosome. This case provides new insight into the genetic causes of disorders of sexual development in humans. (By Dr. Svetlana A. Yatsenko, http://jmg.bmj.com/content/early/2017/05/07/jmedgenet-2016-104128 )

Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa

25 Apr, 17 | by hqqu

Pathogenic variants (mutations) in the Abelson helper integration site 1 (AHI1) gene are known to be associated with Joubert syndrome, a developmental disorder causing visual, cognitive and motor deficits. In this study, we show that some pathogenic variants in the AHI1 gene can cause visual impairment, without other symptoms or signs suggestive of Joubert syndrome. Such variants were located in a specific domain (WD40 domain) of the encoded protein and have only subtle effects when expressed in cells in culture. The data support the hypothesis that these “non-syndromic” variants give residual protein function, while alleles associated with Joubert syndrome completely abolish function. (By Dr. Lonneke Haer-Wigman, http://jmg.bmj.com/content/early/2017/04/25/jmedgenet-2016-104200 )

Confirmation of mutations in PROSC as a novel cause of vitamin B6-dependent epilepsy

8 Apr, 17 | by hqqu

Early onset epilepsy with resistance to common anticonvulsants can be due to genetic defects that respond to high doses of vitamin B6. We describe four patients with neonatal, pyridoxine (vitamin B6) responsive seizures and disease causing variants in the PROSC gene, which regulates vitamin B6 metabolism in body cells. Three patients had favorable outcome with normal intellectual properties at age 12.5, 15.5 and 30 years respectively, while one child had marked developmental delay at age 27 months. Prognosis of patients depends on early treatment with vitamin B6, an essential cofactor for normal brain function, and the underlying PROSC variants. (By Prof. Dr. Barbara Plecko, http://jmg.bmj.com/content/early/2017/04/07/jmedgenet-2017-104521 )

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