Neurodevelopmental disorders are characterized by prevalent neuropsychiatric illnesses with various degrees of social, cognitive, motor, language, and affective deficits. Genetic defects are known to underlie these phenotypes; however, many patients with neurodevelopmental disorders remain without a genetic diagnosis [1]. Next-generation sequencing has provided a powerful tool to identify the underlying genetic causes of these disorders [2].

The PPP2R5D (protein phosphatase 2 regulatory subunit B'delta, Gene ID: 5528, Cytogenetic location: 6p21.1) gene encodes a B56 regulatory subunit of protein phosphatase-2A (PP2A) and is responsible for PPP2R5D-related autosomal dominant mental retardation-35 (MRD35) (Online Mendelian Inheritance in Man (OMIM): 616355) [3], [4], [5], [6]. The clinical features of this neurodevelopmental disorder include mild to severe neurodevelopmental delay, which could be accompanied by language disabilities to varying degrees, hypotonia, macrocephaly, delayed development of motor skill learning in large muscle groups, autism spectrum disorders (ASDs), and other nonspecific clinical manifestations [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16].

MRD35 is a rare autosomal-dominant disease. To date, in the literature, there have been only 106 cases reported worldwide [7], [8], [9], [10], [11], [12], [13], [14], [15], [16] and 4 cases in China [6], [8], [14]. Owing to the lack of familial data and the uncertainty of the phenotypic status of the variation carriers in databases, there have been no data regarding this gene’s penetrance. We searched the literature and all the available databases on the internet (ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/; Decipher: https://www.deciphergenomics.org/gene/PPP2R5D/overview/clinical-info; the Human Gene Mutation Database (HGMD): http://www.hgmd.cf.ac.uk/ac/index.php; Jordan’s Guardian Angels: https://jordansguardianangels.org/research-details-impacts/) and found only two reported families, one with full penetrance [15] and the other with a description of only “paternally inherited”.

We studied 3 generations of a family, including 11 members, 3 of whom were affected by neurodevelopmental disorder. We performed whole-exome sequencing, identified the causal mutation and analysed its cosegregation with the disease phenotypes in the family. Here, we report that a novel pathogenic mutation in PPP2R5D with incomplete penetrance is associated with neurodevelopmental disorder in the pedigree.