Phenotypic characterization of seven individuals with Marbach–Schaaf neurodevelopmental syndrome

• Published in: American journal of medical genetics. Part A Vol. 188; no. 9; pp. 2627 - 2636
• Main Authors: Marbach, Felix, Lipska‐Ziętkiewicz, Beata S., Knurowska, Agata, Michaud, Vincent, Margot, Henri, Lespinasse, James, Tran Mau Them, Frédéric, Coubes, Christine, Park, Joohyun, Grosch, Sarah, Roggia, Cristiana, Grasshoff, Ute, Kalsner, Louisa, Denommé‐Pichon, Anne‐Sophie, Afenjar, Alexandra, Héron, Bénédicte, Keren, Boris, Caro, Pilar, Schaaf, Christian P.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-09-2022; Wiley Subscription Services, Inc; Wiley
• Subjects: Adult; Animal models; Animals; Autism; autism spectrum disorder; Autism Spectrum Disorder - genetics; Catalytic subunits; Central nervous system; Cohort Studies; Development Biology; Embryology and Organogenesis; Genetics; global developmental delay; Human genetics; Humans; Kinases; Life Sciences; Neurobiology; neurodevelopmental disorder; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Neurons and Cognition; pain insensitivity; Patients; Phenotype; Phenotypes; PRKAR1B; Protein kinase A; protein kinase a complex; Syndrome; pain insensitivity; PRKAR1B; autism spectrum disorder; global developmental delay; neurodevelopmental disorder; protein kinase a complex; Global developmental delay; Neurodevelopmental disorder; Autism spectrum disorder; Pain insensitivity; Protein kinase a complex
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.62884

We present the phenotypes of seven previously unreported patients with Marbach–Schaaf neurodevelopmental syndrome, all carrying the same recurrent heterozygous missense variant c.1003C>T (p.Arg335Trp) in PRKAR1B. Clinical features of this cohort include global developmental delay and reduced sensitivity to pain, as well as behavioral anomalies. Only one of the seven patients reported here was formally diagnosed with autism spectrum disorder (ASD), while ASD‐like features were described in others, overall indicating a lower prevalence of ASD in Marbach–Schaaf neurodevelopmental syndrome than previously assumed. The clinical spectrum of the current cohort is similar to that reported in the initial publication, delineating a complex developmental disorder with behavioral and neurologic features. PRKAR1B encodes the regulatory subunit R1β of the protein kinase A complex (PKA), and is expressed in the adult and embryonal central nervous system in humans. PKA is crucial to a plethora of cellular signaling pathways, and its composition of different regulatory and catalytic subunits is cell‐type specific. We discuss potential molecular disease mechanisms underlying the patients' phenotypes with respect to the different known functions of PKA in neurons, and the phenotypes of existing R1β‐deficient animal models.