Alexander Gheldof

Are AZFb deletions always incompatible with sperm production

Deletions on the long arm of the Y chromosome are a well‐known cause of male infertility and it is generally accepted that deletions involving the AZFb region are not compatible with sperm production. Here, we report on two patients for whom basic diagnostic tests showed a deletion of the AZFb region. Unexpectedly, both patients had some residual sperm production. Subsequently, extension and additional analyses of the AZFb region disclosed an aberrant deletion pattern. Therefore, these results emphasize the need for a detailed and powerful analysis of cases where first‐line Yq deletion tests reveal an AZFb deletion. Moreover, our study clearly demonstrated that only a very careful selection of test markers will avoid the pitfall of a ‘no further treatment possible’ wrongful conclusion.

Bi-allelic variants in COL3A1 encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts

Background Collagens are one of the major constituents of the pial membrane, which plays a crucial role in neuronal migration and cortical lamination during brain development. Type III procollagen, the chains of which are encoded by COL3A1, is the ligand of the G protein-coupled receptor 56 (GPR56), also known as adhesion G protein-coupled receptor G1. Bi-allelic mutations in GPR56 give rise to cobblestone-like malformation, white matter changes and cerebellar dysplasia. This report shows that bi-allelic mutations in COL3A1 are associated with a similar phenotype. Methods Exome analysis was performed in a family consisting of two affected and two non-affected siblings. Brain imaging studies of this family and of two previously reported individuals with bi-allelic mutations in COL3A1 were reviewed. Functional assays were performed on dermal fibroblasts. Results Exome analysis revealed a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 of COL3A1. Brain MRI in the affected siblings as well as in the two previously reported individuals with bi-allelic COL3A1 mutations showed a brain phenotype similar to that associated with mutations in GPR56. Conclusion Homozygous or compound heterozygous mutations in COL3A1 are associated with cobblestone-like malformation in all three families reported to date. The variability of the phenotype across patients suggests that genetic alterations in distinct domains of type III procollagen can lead to different outcomes. The presence of cobblestone-like malformation in patients with bi-allelic COL3A1 mutations emphasises the critical role of the type III collagen–GPR56 axis and the pial membrane in the regulation of brain development and cortical lamination.

Sertoli Cell-Only Syndrome: Behind the Genetic Scenes

Sertoli cell-only syndrome is defined by the complete absence of germ cells in testicular tissues and always results in male infertility. The aetiology often remains unknown. In this paper, we have investigated possible causes of Sertoli cell-only syndrome with a special focus on genetic causes. Our results show that, for a large part of the patients (>23% in an unselected group), the sex chromosomes are involved. The majority of patients had a Klinefelter syndrome, followed by patients with Yq microdeletions. Array comparative genomic hybridization in a selected group of “idiopathic patients” showed no known infertility related copy number variations.

Polyneuropathy in a young Belgian patient: A novel heterozygous mutation in the WNK1/HSN2 gene.

Hereditary sensory autonomic neuropathy (HSAN) is a rare condition, predominantly affecting the peripheral sensory nervous system, although variable motor and dysautonomic symptoms can be present. At least 7 clinical types of HSAN have been described, and different genetic mutations have been identified for each of these. HSAN IIA (OMIM #201300) is characterized by loss of pain and loss of temperature and touch sensation, with onset usually before the first decade. The mode of inheritance is autosomal recessive.1 The causative gene, WNK1/HSN2, is located on locus 12p13.33 and is an isoform of the WNK1 (lysine deficient protein kinase 1) gene, which contains the HSN2 exon.2,3 We describe 2 new heterozygous mutations in the WNK1/HSN2 gene in a Belgian patient with early-onset sensory polyneuropathy.

I-PV: a CIRCOS module for interactive protein sequence visualization

SUMMARY Todays genome browsers and protein databanks supply vast amounts of information about proteins. The challenge is to concisely bring together this information in an interactive and easy to generate format. AVAILABILITY AND IMPLEMENTATION We have developed an interactive CIRCOS module called i-PV to visualize user supplied protein sequence, conservation and SNV data in a live presentable format. I-PV can be downloaded from http://www.i-pv.org. CONTACT ibrahim.tanyalcin@i-pv.org, itanyalc@vub.ac.be or support@i-pv.org SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Biallelic mutations in RTTN are associated with microcephaly, short stature and a wide range of brain malformations

Biallelic mutations in the RTTN gene have been reported in association with microcephaly, short stature, developmental delay and malformations of cortical development. RTTN mutations have previously shown to link aberrant ciliary function with abnormal development and organization of the human cerebral cortex. We here report three individuals from two unrelated families with novel mutations in the RTTN gene. The phenotype consisted of microcephaly, short stature, pachygyria or polymicrogyria, colpocephaly, hypoplasia of the corpus callosum and superior vermis. These findings provide further confirmation of the phenotype related to pathogenic variants in RTTN.

Convert your favorite protein modeling program into a mutation predictor: "MODICT".

BackgroundPredict whether a mutation is deleterious based on the custom 3D model of a protein.ResultsWe have developed modict, a mutation prediction tool which is based on per residue rmsd (root mean square deviation) values of superimposed 3D protein models. Our mathematical algorithm was tested for 42 described mutations in multiple genes including renin (REN), beta-tubulin (TUBB2B), biotinidase (BTD), sphingomyelin phosphodiesterase-1 (SMPD1), phenylalanine hydroxylase (PAH) and medium chain Acyl-Coa dehydrogenase (ACADM). Moreover, modict scores corresponded to experimentally verified residual enzyme activities in mutated biotinidase, phenylalanine hydroxylase and medium chain Acyl-CoA dehydrogenase. Several commercially available prediction algorithms were tested and results were compared. The modictperl package and the manual can be downloaded from https://github.com/IbrahimTanyalcin/MODICT.ConclusionsWe show here that modict is capable tool for mutation effect prediction at the protein level, using superimposed 3D protein models instead of sequence based algorithms used by polyphen and sift.

PP05.6 – 2896: Genotype-phenotype correlations and counseling in carriers of Filamin A gene mutations

Objective Mutations in the X-linked gene Filamin A (FLNA) are known to be linked to a broad clinical phenotype ranging from otopalatodigital syndromes (OPD1, OPD2) to frontometaphyseal dysplasia, Melnick-Needles syndrome and periventricular nodular heterotopia (PVNH). In the present study we investigate the phenotype-genotype correlation in carriers of FLNA mutations in order to improve the counseling of these patients and their relatives. Methods Clinical and neuroloradiological data from 16 FLNA mutation carriers were collected through retrospective analysis of their hospital files and a standardized questionnaire sent to the referring physician. These data were reviewed by a neurologist, molecular geneticists and a clinical geneticist. Results Fifteen of the carriers were female, as expected in dominant X-linked disorders. Half of the carriers belonged to a mother-child pair, with the mother being diagnosed secondary to the diagnosis in the child. Four carriers had the clinical diagnosis of OPD and their mutations were clustered in exons 3 and 4, whereas the mutations associated with PVNH were scattered throughout the gene. Besides the PVNH other findings on brain MRI included mega cisterna magna, corpus callosum and white matter anomalies. Cardiac investigations revealed aortic valve insufficiency and dilatation of the aorta, even at young age. In the majority of the patients, the clinical work-up focused on the primary indications for FLNA mutation analysis whereby other organs were not systematically investigated. Conclusion Although a lot is already known on the manifestations caused by FLNA mutations, and phenotype-genotype correlations can be made to a certain extent, many patients could benefit from a more extensive work-up and follow-up. This will not only lead to further improvement of our knowledge and understanding of the FLNA-related disorders, but will also allow us to anticipate on certain complications.