Genetic modifiers and ascertainment drive variable expressivity of complex disorders

Matthew Jensen ^1 2, Corrine Smolen ^1 2, Anastasia Tyryshkina ¹, Lucilla Pizzo ¹, Deepro Banerjee ¹, Matthew Oetjens ³, Hermela Shimelis ³, Cora M Taylor ³, Vijay Kumar Pounraja ^1 2, Hyebin Song ⁴, Laura Rohan ¹, Emily Huber ¹, Laila El Khattabi ⁵, Ingrid van de Laar ⁶, Rafik Tadros ⁶, Connie Bezzina ⁶, Marjon van Slegtenhorst ⁶, Janneke Kammeraad ⁶, Paolo Prontera ⁷, Jean-Hubert Caberg ⁸, Harry Fraser ⁹, Siddhartha Banka ^9 10, Anke Van Dijck ¹¹, Charles Schwartz ¹², Els Voorhoeve ¹³, Patrick Callier ¹⁴, Anne-Laure Mosca-Boidron ¹⁴, Nathalie Marle ¹⁴, Mathilde Lefebvre ¹⁵, Kate Pope ¹⁶, Penny Snell ¹⁶, Amber Boys ¹⁶, Paul J Lockhart ^16 17, Myla Ashfaq ¹⁸, Elizabeth McCready ¹⁹, Margaret Nowacyzk ¹⁹, Lucia Castiglia ²⁰, Ornella Galesi ²⁰, Emanuela Avola ²⁰, Teresa Mattina ²⁰, Marco Fichera ^20 21, Maria Grazia Bruccheri ²⁰, Giuseppa Maria Luana Mandarà ²², Francesca Mari ²³, Flavia Privitera ²³, Ilaria Longo ²³, Aurora Curró ²³, Alessandra Renieri ²³, Boris Keren ²⁴, Perrine Charles ²⁴, Silvestre Cuinat ²⁵, Mathilde Nizon ²⁵, Olivier Pichon ²⁵, Claire Bénéteau ²⁵, Radka Stoeva ²⁵, Dominique Martin-Coignard ²⁶, Sophia Blesson ²⁷, Cedric Le Caignec ^28 29, Sandra Mercier ²⁷, Marie Vincent ²⁷, Christa Martin ³, Katrin Mannik ^30 31, Alexandre Reymond ³², Laurence Faivre ^14 15, Erik Sistermans ¹³, R Frank Kooy ¹¹, David J Amor ¹³, Corrado Romano ^20 21, Joris Andrieux ³³, Santhosh Girirajan ^1 2 34

[Preprint]. 2024 Aug 28:2024.08.27.24312158.

 doi: 10.1101/2024.08.27.24312158.

• PMID: 39252907
• PMCID: PMC11383473
• DOI: 10.1101/2024.08.27.24312158

Abstract

Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants towards clinical outcomes of 2,252 individuals with primary variants. Among 132 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risk for specific developmental features, including short tandem repeats for neurological defects and SNVs for microcephaly, while additional disease-associated variants conferred multiple genetic diagnoses. Within disease and population cohorts of 773 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants towards clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as 16p11.2 deletion and CHD8 variants, and 1,084 without primary variants, showed that phenotypic associations differed by primary variant context and were influenced by synergistic interactions between primary and secondary variants. Our study provides a paradigm to dissect the genomic architecture of complex disorders towards personalized treatment.

Cortical miR-709 links glutamatergic signaling to NREM sleep EEG slow waves in an activity-dependent manner

Konstantinos Kompotis ^# 1 2, Géraldine M Mang ^# 1, Jeffrey Hubbard ¹, Sonia Jimenez ¹, Yann Emmenegger ¹, Christos Polysopoulos ³, Charlotte N Hor ¹, Leonore Wigger ⁴, Sébastien S Hébert ^5 6, Valérie Mongrain ^7 8 9, Paul Franken ¹

. 2024 Jan 16;121(3):e2220532121.

 doi: 10.1073/pnas.2220532121. Epub 2024 Jan 11.

• PMID: 38207077
• DOI: 10.1073/pnas.2220532121

Free article

Abstract

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that have been implicated in a plethora of neuronal processes. Nevertheless, their role in regulating brain activity in the context of sleep has so far received little attention. To test their involvement, we deleted mature miRNAs in post-mitotic neurons at two developmental ages, i.e., in early adulthood using conditional Dicer knockout (cKO) mice and in adult mice using an inducible conditional Dicer cKO (icKO) line. In both models, electroencephalographic (EEG) activity was affected and the response to sleep deprivation (SD) altered; while the rapid-eye-movement sleep (REMS) rebound was compromised in both, the increase in EEG delta (1 to 4 Hz) power during non-REMS (NREMS) was smaller in cKO mice and larger in icKO mice compared to controls. We subsequently investigated the effects of SD on the forebrain miRNA transcriptome and found that the expression of 48 miRNAs was affected, and in particular that of the activity-dependent miR-709. In vivo inhibition of miR-709 in the brain increased EEG power during NREMS in the slow-delta (0.75 to 1.75 Hz) range, particularly after periods of prolonged wakefulness. Transcriptome analysis of primary cortical neurons in vitro revealed that miR-709 regulates genes involved in glutamatergic neurotransmission. A subset of these genes was also affected in the cortices of sleep-deprived, miR-709-inhibited mice. Our data implicate miRNAs in the regulation of EEG activity and indicate that miR-709 links neuronal activity during wakefulness to brain synchrony during sleep through the regulation of glutamatergic signaling.