Bioscientia human geneticists reveal hidden co-inheritance of two recessive conditions by PacBio genome sequencing
In the current issue of Human Genetics and Genomics Advances, human geneticists from Bioscientia, Ingelheim (Germany) report “en bloc” inheritance of point mutations in adjacent genes which has rarely been described. They report a family with severe, mostly early-lethal Joubert syndrome (JBTS) with early-onset severe retinal dystrophy (EOSRD) and polycystic kidney disease (PKD), which had been described and published previously. At that time, the phenotype had been attributed to a mutation in the POC1B gene. Because POC1B variants have since then only been associated with non-syndromic childhood or early-adult-onset macular dystrophy, the team now reassessed the index patient by long-read genome sequencing (LR-WGS) on a PacBio Revio and identified a homozygous deep-intronic variant in CEP290, a JBTS/Meckel syndrome gene, in only 1.28 Mb distance from POC1B. cDNA analysis revealed aberrant splicing with frame-shifting inclusion of a poison exon. EOSRD and PKD can be fully ascribed to this CEP290 variant, whose effect outshines the “background” non-syndromic POC1B retinopathy. This co-inheritance of two ciliopathies, with the clinically decisive variant hidden deep in an intron, exemplifies the importance of WGS for achieving the complete diagnosis in challenging cases.
Friday, July 25, 2025
New genetic tumor syndrome identified
In an international study led by Prof. Dr. Hanno Bolz, mutations in the MAD2L1BP gene have been identified as the cause of a new tumor syndrome. The genetic defect leads to chromosomal maldistribution in a large proportion of cells in those affected; the resulting disease is therefore classified as mosaic variegated aneuploidy (MVA).
The MAD2L1BP protein is part of a dynamic protein complex that controls correct chromosome segregation. Its impairment leads to MVA in an Egyptian patient and her affected brother. Aneuploidies are considered a risk factor for cancer development, and the siblings actually developed extremely rare gonadal tumors in early childhood, a juvenile granulosa cell tumor (JGCT) of the ovary or testis.
A Saudi patient with a pronounced brain malformation, severe developmental disorder and epilepsy (which were also present in the Egyptian patient) died very early and possibly before a tumor could develop. This patient, but not the Egyptian siblings, also exhibited repeated blood sugar abnormalities, which have also been described in mice with an inactivated MAD2L1BP gene.
Together with partners from the University of Bayreuth and the University Medical Center Mainz, the cellular effects of the genetic defect were characterized in functional detail. The study provides important new insights into hereditary tumor diseases, a diagnostic, advisory and scientific focus of Bioscientia Human Genetics.
The publication can be read in the specialist journal JCI Insight.
If you have any questions about the publication, please contact Prof. Dr. Hanno Bolz by e-mail: hanno.bolz@bioscientia.de. If you have any questions about human genetic counseling and diagnostics, please contact the Bioscientia Human Genetics team.
Text by: Laura Ranzenberger
Tuesday, October 17, 2023
New cause of retinal dystrophy identified
In an international study led by Prof. Dr. Hanno Bolz, Medical Director of Bioscientia Human Genetics since the beginning of 2023, mutations in the CEP162 gene have been identified as a new cause of retinitis pigmentosa (RP). RP is the most common form of hereditary retinal degeneration.
Together with partners, particularly from the USA and Belgium, it was possible to show in detail how the CEP162 defect leads to a gradual loss of function of the retinal cells. The consequences are night blindness, progressive narrowing of the visual field and ultimately almost complete loss of vision.
The study was the result of routine diagnostics in which no cause was found in the known RP genes. The intensive search for the genetic basis led to the identification of a previously unknown cause of RP. This procedure is exemplary for Bioscientia's human genetics department, as hereditary eye diseases (especially retinal diseases) are a diagnostic, counseling and scientific focus.
Benefits for patients
The identification of the gene closes another gap. Thanks to the publication, CEP162 is now being used in diagnostics worldwide. This means that patients with RP caused by a defect in the CEP162 gene now also receive a clear genetic diagnosis.
With a clear diagnosis, the prognosis can be assessed better and the risk of recurrence can be determined (in this case: very low risk of recurrence of the disease in the patients' own children). In addition, those affected can register in patient registers (e.g. that of PRO RETINA) in order to benefit from future therapeutic approaches as early as possible. Furthermore, the identification of a causative gene is the first prerequisite for the development of a gene-specific therapeutic approach. The publication can be read in the Journal of Clinical Investigation.
If you have any questions about the publication, please contact Prof. Dr. Hanno Bolz by e-mail: hanno.bolz@bioscientia.de.
If you have any questions about human genetic counseling and diagnostics, please contact the Bioscientia Human Genetics team.
Text by: Laura Ranzenberger
Monday, June 12, 2023