Search

Biallelic pathogenic variants in ALDH1A3 are responsible for approximately 11% of recessively inherited cases of severe developmental eye anomalies. Some individuals can display variable neurodevelopmental features, but the relationship to the ALDH1A3 variants remains unclear. Here, we describe seven unrelated families with biallelic pathogenic ALDH1A3 variants: four compound heterozygous and three homozygous. All affected individuals had bilateral anophthalmia/microphthalmia (A/M), three with additional intellectual or developmental delay, one with autism and seizures and three with facial dysmorphic features. This study confirms that individuals with biallelic pathogenic ALDH1A3 variants consistently manifest A/M, but additionally display neurodevelopmental features with significant intra- and interfamilial variability. Furthermore, we describe the first case with cataract and highlight the importance of screening ALDH1A3 variants in nonconsanguineous families with A/M.

We report on an 8-year-old girl with severe developmental and epileptic encephalopathy due to the compound heterozygous null variants p.(Gln661*) and p.(Leu830Profs*2) in GRIN2A resulting in a knockout of the human GluN2A subunit of the N-methyl-D-aspartate receptor. Both parents had less severe GRIN2A-related phenotypes and were heterozygous carriers of the respective null variant. Functional investigations of both variants suggested a loss-of-function effect. This is the first description of an autosomal recessive, biallelic type of GRIN2A-related disorder. Nonetheless, there are marked parallels to two previously published families with severe epileptic encephalopathy due to homozygous null variants in GRIN1 as well as various knockout animal models. Compared to heterozygous null variants, biallelic knockout of either GluN1 or GluN2A is associated with markedly more severe phenotypes in both humans and mice. Furthermore, recent findings enable a potential precision medicine approach targeting GRIN-related disorders due to null variants.

There is a need to standardise, within a coordinated Swiss framework, the practical aspects of genetic testing and genetic counselling on possibly inherited cardiovascular disorders in relatives of a sudden cardiac death (SCD) victim. Because of the major advances in genetic investigation techniques and recent publication of international guidelines in the field of cardiology, genetics and pathology, we consider it important to summarise the current evidence and propose an optimal approach to post-mortem genetic investigation for SCD victims and their families in Switzerland. In this article, we discuss important technical, financial and medico-ethical aspects, and provide updated information on specific situations in which forensic pathologists, general practitioners and cardiologists should suspect a genetic origin of the SCD. At present, the principles of benefit, the duty to warn and the impact of genetic information for family members at risk are considered as strong justifications for post-mortem disclosure and prevail over the arguments of respect for a deceased person’s privacy and confidentiality. This paper underlines also the need to update and improve the general knowledge concerning the genetic risk of cardiovascular pathologies, the importance to perform an autopsy and post-mortem genetic testing in SCD victims, and to develop standardized post-mortem disclosure policy at national and international levels for SCD cases and relatives.