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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 )

Somatic mosaicism containing double mutations in PTCH1 revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome

31 Mar, 17 | by hqqu

As next generation sequencers are widely used, somatic mosaicism is thought to be more common than previously expected. We report a mosaic patient with nevoid basal cell carcinoma syndrome, a genetic condition featured by minor anomalies and high prevalence of cancers such as basal cell carcinoma and medulloblastoma. The patient had a germline PTCH1 mutation, c.272delG, and a low prevalence somatic mutation, c.274delT. Since two mutations are located in close proximity, reversion error is likely to be involved in this event rather than a spontaneous mutation. This study is also unique in that mosaicism was initially identified by analysis of iPS cell clones derived from a single cell. (By Prof. Toshiyuki Miyashita, http://jmg.bmj.com/content/early/2017/03/31/jmedgenet-2016-104490 )

Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus

13 Mar, 17 | by hqqu

One of the major susceptibility loci identified for Systemic lupus erythematosus (SLE) lies within a common large inversion polymorphism region on chromosome 8p23. In this study, we further investigated the ‘extended’ 8p23 locus (~4 Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery dataset (~1,200 subjects) and a replication dataset (>10,000 subjects) comprising European-descent individuals. Our results have implicated multiple (known+novel) SLE signals/genes at the extended 8p23 locus and suggested that this broad locus contributes to SLE risk through the effects of multiple genes/pathways. Our findings underline the importance of evaluating the entire inversion region for any disease/trait linked to this 8p23 locus. (By Dr. F. Yesim Demirci, http://jmg.bmj.com/content/early/2017/03/13/jmedgenet-2016-104247 )

15 years of research on Oral-Facial-Digital syndromes: from 1 to 16 causal genes

13 Mar, 17 | by hqqu

Oral-facial-digital syndromes (OFDS) are rare genetic disorders characterized by the association of abnormalities of the face, oral cavity and extremities. Molecular bases were poorly known but we suspected the involvement of ciliary genes. Using whole-exome sequencing in 24 OFDS cases, we identified causal variants in five new genes, two genes previously implicated in OFDS and four genes previously related to other ciliopathies. Functional studies revealed the involvement of several structural or functional defects of primary cilia (centrosome, transition zone, intraflagellar transport), and characterized three ciliary protein complexes. (By Dr. Ange-Line Bruel, http://jmg.bmj.com/content/early/2017/03/12/jmedgenet-2016-104436 )

Novel and known ribosomal causes of Diamond-Blackfan anemia identified through comprehensive genomic characterization

9 Mar, 17 | by hqqu

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome primarily caused by defects in ribosome biology. It is associated with physical anomalies and high risk of specific cancers. We performed comprehensive genomic analyses of 35 genetically uncharacterized DBA families participating in the National Cancer’s Institute’s DBA cohort (ClinicalTrials.gov Identifier: NCT00027274). Using whole exome sequencing, copy number variation and array comparative genomic hybridization, we discovered variants in two genes not previously associated with DBA, RPL18 and RPL35. These variants caused characteristic ribosome assembly defects consistent with the DBA biology. Overall, this combination of genomic methods led to the identification the causative variant in 72% of the cohort. Efforts are underway to identify the underlying genetic cause of DBA in the remaining families. (By Dr. Payal P. Khincha, http://jmg.bmj.com/content/early/2017/03/09/jmedgenet-2016-104346 )

A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis

6 Mar, 17 | by hqqu

Hydranencephaly, a congenital anomaly caused by destruction of the cerebral hemispheres is usually found in isolation. We report a family in which three fetuses displayed multinucleated neurons, anhydramnios, renal dysplasia, and cerebellar hypoplasia together with hydranencephaly, a novel syndrome we have named MARCH. Sequencing revealed the cause to be a homozygous truncating mutation in CEP55, a cell cycle regulator. Knock-down of the CEP55 ortholog in zebrafish reproduced the brain and kidney defects, and were rescued by full-length, but not truncated human CEP55. When we expressed truncated CEP55 in human cells, the protein failed to localize properly, producing multinucleated daughter cells. Our results implicate a faulty centrosomal protein as the cause of this lethal multiple anomaly syndrome. (By Dr. Patrick Frosk, http://jmg.bmj.com/content/early/2017/03/06/jmedgenet-2016-104296 )

Zebrafish were used to model MARCH syndrome, a novel multi system disorder in humans caused by mutations in CEP55. Image credits to Carter Gunn, Julien Philippe (microscopy), and Abigaëlle Philippe (center image)

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