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Increased Breast Cancer Risk in MSH2 Carriers from a Large Canadian Familial Cancer Registry

4 Aug, 17 | by hqqu

Lynch Syndrome is an inherited condition involving several well-characterized mutations; MLH1, MSH2, MSH6, and PMS2. Affected families are counselled on their increased risk of numerous malignant diagnoses including colorectal cancer and endometrial cancer, as well as central nervous system malignancies and several other gastrointestinal and genitourinary cancers. Management of Lynch Syndrome includes prevention and surveillance, such as colonoscopies for early detection of colorectal cancer, and prophylactic hysterectomy for endometrial cancer.

There is a suggestion that Lynch Syndrome may confer an increased risk of breast cancer, however the literature remains conflicting. Our work identified an increased risk in MSH2 carrier women in a large Canadian registry (SIR 3.11 (95%CI: 1.95-4.71), lifetime cumulative incidence 22%). Furthermore, we have demonstrated the high penetrance of Lynch Syndrome cancers within their individual family pedigrees, and that similar to other Lynch Syndrome diagnoses, breast cancers occur at a younger age compared to the unaffected Canadian population. Ours is the first study to demonstrate an association between breast cancer risk and family history of Lynch Syndrome-related malignancies, and reports on a large number of breast cancer events compared to many published series.

Identification of breast cancer as a Lynch Syndrome related malignancy could have significant implications for mutation carriers. Effective surveillance and prevention strategies are available and could be further explored. These interventions have proven beneficial in other high-risk populations, such as BRCA1/2 carriers. (By Dr. Mira Goldberg, http://jmg.bmj.com/content/early/2017/08/04/jmedgenet-2017-104542 )

Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders

28 Jul, 17 | by hqqu

Mitochondrial cytopathies are genetic diseases, some of which result from mutations affecting part of the multiple DNA molecules located within mitochondria (mtDNA). Coexistence of mutant and wild-type mtDNA molecules is called “heteroplasmy” and defines a “mutant load”. Disease symptoms occur when the mutant load surpasses a tissue-specific threshold.

Owing to the absence of therapy and the high recurrence risk for these serious diseases, at-risk couples commonly request a prenatal diagnosis, based on determination of the mutant load on a single chorionic villous sample (CVS). We have shown that this mutant load is widely heterogeneous within placentas, so that mutant load determined from CVS should be interpreted with caution and associated to/substituted by a mutant load measurement on amniocytes. (By Drs. Julie Steffann and Jean-Paul Bonnefont, http://jmg.bmj.com/content/early/2017/07/27/jmedgenet-2017-104615 )

A germline deletion of 9p21.3 presenting as familial melanoma, astrocytoma and breast cancer: clinical and genetic counselling challenges

28 Jul, 17 | by hqqu

Very few families with 9p21.3 deletion have been described. These families are at risk of developing melanoma and nerve sheath tumors.  We report a family with several members affected by melanoma, astrocytoma, neurofibromas, and breast cancer. They have a 9p21.3 deletion containing 9 genes. While mutations within individual genes are associated with distinct hereditary cancer syndromes, we do not know what kinds of tumors can occur when several genes are missing. This complex case illustrates the need for healthcare providers trained in genetics to be involved in hereditary cancer testing, which is becoming increasingly utilized in various clinical settings. (by Dr. Jaime Vengoechea and Christine Tallo, MMSc, CGC, http://jmg.bmj.com/content/early/2017/07/27/jmedgenet-2017-104690 )

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 )

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