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Leigh syndrome spectrum (LSS) is a primary mitochondrial disorder defined neuropathologically by a subacute necrotizing encephalomyelopathy and characterized by bilateral basal ganglia and/or brainstem lesions. LSS is associated with variants in several mitochondrial DNA genes and more than 100 nuclear genes, most often related to mitochondrial complex I (CI) dysfunction. Rarely, LSS has been reported in association with primary Leber hereditary optic neuropathy (LHON) variants of the mitochondrial DNA, coding for CI subunits (m.3460G>A in MT-ND1, m.11778G>A in MT-ND4 and m.14484T>C in MT-ND6). The underlying mechanism by which these variants manifest as LSS, a severe neurodegenerative disease, as opposed to the LHON phenotype of isolated optic neuropathy, remains an open question. Here, we analyse the exome sequencing of six probands with LSS carrying primary LHON variants, and report digenic co-occurrence of the m.11778G > A variant with damaging heterozygous variants in nuclear disease genes encoding CI subunits as a plausible explanation. Our findings suggest a digenic mechanism of disease for m.11778G>A-associated LSS, consistent with recent reports of digenic disease in individuals manifesting with LSS due to biallelic variants in the recessive LHON-associated disease gene DNAJC30 in combination with heterozygous variants in CI subunits., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying numerous disease-associated genes and significantly enlarged our knowledge in the field of human genetics, it has limitations in explaining phenomena like phenotypic variability and reduced penetrance. Widening the perspective beyond Mendelian inheritance has the potential to enable a better understanding of disease complexity in rare disorders. Digenic inheritance is the simplest instance of a non-Mendelian disorder, characterized by the functional interplay of variants in two disease-contributing genes. Known digenic disease causes show a range of pathomechanisms underlying digenic interplay, including direct and indirect gene product interactions as well as epigenetic modifications. This review aims to systematically explore the background of digenic inheritance in rare disorders, the approaches and challenges when investigating digenic inheritance, and the current evidence for digenic inheritance in mitochondrial disorders.

STAG2 is a component of the large, evolutionarily highly conserved cohesin complex, which has been linked to various cellular processes like genome organization, DNA replication, gene expression, heterochromatin formation, sister chromatid cohesion, and DNA repair. A wide spectrum of germline variants in genes encoding subunits or regulators of the cohesin complex have previously been identified to cause distinct but phenotypically overlapping multisystem developmental disorders belonging to the group of cohesinopathies. Pathogenic variants in STAG2 have rarely been implicated in an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphic features. Here, we describe for the first time a mosaic STAG2 variant in an individual with developmental delay, microcephaly, and hemihypotrophy of the right side. We characterized the grade of mosaicism by deep sequencing analysis on DNA extracted from EDTA blood, urine and buccal swabs. Furthermore, we report an additional female with a novel de novo splice variant in STAG2 . Interestingly, both individuals show supernumerary nipples, a feature that has not been reported associated to STAG2 before. Remarkably, additional analysis of STAG2 transcripts in both individuals showed only wildtype transcripts, even after blockage of nonsense-mediated decay using puromycin in blood lymphocytes. As the phenotype of STAG2 -associated cohesinopathies is dominated by global developmental delay, severe microcephaly, and brain abnormalities, we investigated the expression of STAG2 and other related components of the cohesin complex during Bioengineered Neuronal Organoids (BENOs) generation by RNA sequencing. Interestingly, we observed a prominent expression of STAG2 , especially between culture days 0 and 15, indicating an essential function of STAG2 in early brain development. In summary, we expand the genotypic and phenotypic spectrum of STAG2 -associated cohesinopathies and show that BENOs represent a promising model to gain further insights into the critical role of STAG2 in the complex process of nervous system development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schmidt, Dreha-Kulaczewski, Zafeiriou, Schreiber, Wilken, Funke, Neuhofer, Altmüller, Thiele, Nürnberg, Biskup, Li, Zimmermann, Kaulfuß, Yigit and Wollnik.)

Objective: Clinical, neuroimaging, and genetic characterization of 3 patients with LINS1 -associated developmental regression, intellectual disability, dysmorphism, and further neurologic deficits., Methods: Three affected brothers from a consanguineous family from Afghanistan, their 2 healthy siblings, and both parents were all assessed in the clinic. General and neurologic examination, expert dysmorphology examination, and 3T brain MRI were performed. Whole-exome sequencing was performed for the 3 affected brothers, followed by Sanger sequencing in all available family members., Results: The index patient and his 2 affected brothers presented a complex neurologic syndrome with similar features but marked intrafamilial phenotypical variability, including varying degrees of cognitive impairment, speech impairment, dystonia, abnormal eye movements, and dysmorphic features. All 3 affected brothers are homozygous for a novel, pathogenic frameshift mutation in LINS1 , c.1672_1679del, and p.Gly558Pro fs *22, whereas both parents and healthy siblings are heterozygous for the mutation. No major brain malformations were evident in 3T brain MRI of the affected brothers., Conclusion: This consanguineous family with a novel mutation expands the spectrum of LINS1 -associated disorder to include developmental regression, oculomotor signs, and dystonia, previously not described in the published 9 cases of this rare disorder. The 3T-MRI data from our 3 patients and review of the neuroimaging data in the literature showed unspecific brain MRI changes. LINS1 protein is a known modulating factor of the Wnt signaling pathway, with important roles in organogenesis including of the cerebral cortex. More research is warranted to disentangle the underlying pathophysiologic mechanisms, leading to cognitive impairment and the complex phenotype of LINS1 -associated disorder., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) is a rare disease caused by mutations in the X chromosomal PIGA gene. Clinically it is characterized by early-onset epilepsy, hypotonia, dysmorphic features, and variable congenital anomalies. PIGA codes for the phosphatidylinositol glycan-class A protein, which forms a subunit of an enzymatic complex involved in glycophosphatidylinositol (GPI) biosynthesis. We present a new case of MCAHS2 and perform a comprehensive review of the available literature to delineate the phenotypical traits associated with germline PIGA mutations. Furthermore, we provide functional evidence of pathogenicity of the novel missense mutation, c.154C>T; (p.His52Tyr), in the PIGA gene causative of MCAHS2 in our patient. By flow cytometry, we observed reduced expression of GPI-anchored surface proteins in patient granulocytes compared to control samples, proving GPI-biogenesis impairment. The patient's severe epilepsy with several daily attacks was refractory to treatment, but the frequency of seizures reduced temporarily under triple therapy with perampanel, rufinamide and vigabatrin. Our study delineates the known MCAHS2 phenotype and discusses challenges of diagnosis and clinical management in this complex, rare disease. Furthermore, we present a novel mutation with functional evidence of pathogenicity., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by S. Karger AG, Basel.)

Objective: Pheochromocytomas (PCCs) are neuroendocrine tumors that occur in the adrenal medulla, whereas paragangliomas (PGLs) arise from paraganglia in the head, neck, thorax, or abdomen. In a variety of tumors, cancer cells with stem cell-like properties seem to form the basis of tumor initiation because of their ability to self-renew and proliferate. Specifically targeting this small cell population may lay the foundation for more effective therapeutic approaches. In the present study, we intended to identify stem cells in PCCs/PGLs., Design: We examined the immunohistochemical expression of 11 stem cell markers (SOX2, LIN28, NGFR, THY1, PREF1, SOX17, NESTIN, CD117, OCT3/4, NANOG, and CD133) on tissue microarrays containing 208 PCCs/PGLs with different genetic backgrounds from five European centers., Results: SOX2, LIN28, NGFR, and THY1 were expressed in more than 10% of tumors, and PREF1, SOX17, NESTIN, and CD117 were expressed in <10% of the samples. OCT3/4, NANOG, and CD133 were not detectable at all. Double staining for chromogranin A/SOX2 and S100/SOX2 demonstrated SOX2 immunopositivity in both tumor and adjacent sustentacular cells. The expression of SOX2, SOX17, NGFR, LIN28, PREF1, and THY1 was significantly associated with mutations in one of the succinate dehydrogenase (SDH) genes. In addition, NGFR expression was significantly correlated with metastatic disease., Conclusion: Immunohistochemical expression of stem cell markers was found in a subset of PCCs/PGLs. Further studies are required to validate whether some stem cell-associated markers, such as SOX2, could serve as targets for therapeutic approaches and whether NGFR expression could be utilized as a predictor of malignancy., (© 2015 European Society of Endocrinology.)