Neurodevelopmental Genetic Diseases Associated With Microdeletions and Microduplications of Chromosome 17p13.3

Abstract

Chromosome 17p13.3 is a region of genomic instability that is linked to different rare neurodevelopmental genetic diseases, depending on whether a deletion or duplication of the region has occurred. Chromosome microdeletions within 17p13.3 can result in either isolated lissencephaly sequence (ILS) or Miller-Dieker syndrome (MDS). Both conditions are associated with a smooth cerebral cortex, or lissencephaly, which leads to developmental delay, intellectual disability, and seizures. However, patients with MDS have larger deletions than patients with ILS, resulting in additional symptoms such as poor muscle tone, congenital anomalies, abnormal spasticity, and craniofacial dysmorphisms. In contrast to microdeletions in 17p13.3, recent studies have attracted considerable attention to a condition known as a 17p13.3 microduplication syndrome. Depending on the genes involved in their microduplication, patients with 17p13.3 microduplication syndrome may be categorized into either class I or class II. Individuals in class I have microduplications of the YWHAE gene encoding 14-3-3ε, as well as other genes in the region. However, the PAFAH1B1 gene encoding LIS1 is never duplicated in these patients. Class I microduplications generally result in learning disabilities, autism, and developmental delays, among other disorders. Individuals in class II always have microduplications of the PAFAH1B1 gene, which may include YWHAE and other genetic microduplications. Class II microduplications generally result in smaller body size, developmental delays, microcephaly, and other brain malformations. Here, we review the phenotypes associated with copy number variations (CNVs) of chromosome 17p13.3 and detail their developmental connection to particular microdeletions or microduplications. We also focus on existing single and double knockout mouse models that have been used to study human phenotypes, since the highly limited number of patients makes a study of these conditions difficult in humans. These models are also crucial for the study of brain development at a mechanistic level since this cannot be accomplished in humans. Finally, we emphasize the usefulness of the CRISPR/Cas9 system and next generation sequencing in the study of neurodevelopmental diseases.

Phenotype‐to‐genotype approach reveals head‐circumference‐associated genes in an autism spectrum disorder cohort

“…31 Chromosome 17p13.3 duplication causes multiple complex NDD phenotypes, including mild to severe developmental phenotypes, ASD, and mild brain malformations including microcephaly. 2 Our patient presents with ASD, ID, language developmental delay, abnormal MRI, and ADHD. All these phenotypes were recurrently observed in reported patients with chromosome 17p13.3…”

“…1 Besides the core symptoms, a deficit in social communication and restricted and repetitive behaviors, ASD has a large group of clinical manifestations, such as language disability, intellectual disability (ID), seizure, abnormal head size, gastrointestinal (GI) problems, etc. 2 To date, de novo and rare gene-disruptive mutations and copy number variants (CNVs) have been found to contribute a significant proportion to the ASD genetic architecture. 3 However, because of the extremely rare variants of each gene, very large cohorts are needed to prove the significance of an individual gene.…”

PEDF-Rpsa-Itga6 signaling regulates cortical neuronal morphogenesis

“…MDS has a complex etiology because it caused by a microdeletion that could include more than 26 genes, including Serpinf1 . While most of the genes deleted in MDS patients have not been investigated, previous studies have analyzed some genes, including Pafah1b1 (Lis1), Ywhae (14-3-3ε) and Crk in the MDS critical region (22, 39–43). However, these studies focused on the gene functions in neuronal migration and neural activity, since most MDS patients suffer from epilepsy.…”

“…PEDF expression declines with age and is downregulated by more than 100-fold in aged human fibroblast as compared to young human fibroblast, suggesting an important role for PEDF in early development (21). Additionally, Serpinf1 , coding for the PEDF protein, is encoded in a clinically relevant region of chromosome 17p13.3 known as the Miller-Dieker Syndrome critical region that is frequently deleted or duplicated in a variety of neurodevelopmental disorders (22, 23). Thus, the relationship between PEDF and its receptor Rpsa in the developing cortex is of interest.…”

14-3-3 shuttles Activity-dependent neuroprotective protein to the cytoplasm to promote appropriate neuronal morphogenesis, cortical connectivity and calcium signaling

“…Furthermore, our in vivo staining patterns reveal Adnp is located exclusively in the cytoplasm of neurons in the cortex at P15, which is when our morphological analyses took place. 14-3-3 proteins are well known nuclear-cytoplasmic shuttles that are crucial for neuronal development and neurite formation (8, 41, 55, 77–79). By expressing a global 14-3-3 isoform inhibitor in primary cortical neurons we trapped the majority of Adnp in the nucleus, resulting in cells with Adnp localization that was similar to that of neuronal stem cells.…”