Neurodevelopmental Disorders Associated with Abnormal Gene Dosage: Smith–Magenis and Potocki–Lupski Syndromes

Abstract

Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6 Mb microduplication of 17p11.2, known as PTLS, represents the mechanistically predicted homologous recombination reciprocal of the SMS microdeletion, both resulting in multiple congenital anomalies. Mouse model studies have revealed that the retinoic acid-inducible 1 gene (RAI1) within the SMS and PTLS critical genomic interval is the dosage-sensitive gene responsible for the major phenotypic features in these disorders. Even though PTLS and SMS share the same genomic region, clinical manifestations and behavioral issues are distinct and in fact some mirror traits may be on opposite ends of a given phenotypic spectrum. We describe the neurobehavioral phenotypes of SMS and PTLS patients during different life phases as well as clinical guidelines for diagnosis and a multidisciplinary approach once diagnosis is confirmed by array comparative genomic hybridization or RAI1 gene sequencing. The main goal is to increase awareness of these rare disorders because an earlier diagnosis will lead to more timely developmental intervention and medical management which will improve clinical outcome.

MYT1L: A systematic review of genetic variation encompassing schizophrenia and autism

“…Gain of function of SCN2A is associated with early onset epilepsy, while loss of function of SCN2A is associated with autism or later onset epilepsy (Heyne et al, ). Finally, duplication of RAI1 in mice has been associated with hyperactivity while loss of function in mice has been associated with obesity and abnormal EEG patterns (Neira‐Fresneda & Potocki, ). Each of these associations, individually considered with respect to deletion or duplication, can be categorized as following Deshpande and Weiss' dominant model of gene expression in which gain or loss of copy number is associated with one phenotype, while the opposite direction of gene expression has no effect on that phenotype, but rather influences an alternate phenotype (Deshpande & Weiss, ).…”

A New Patient with Potocki–Lupski Syndrome: A Literature Review

“…We cannot exclude the possibility that variant alleles on the nonrearranged chromosome may contribute to the heterogeneous clinical presentations of the two syndromes. 12 As this genomic region is rich in low-copy repeats both larger and smaller recurrent duplications, as well as nonrecurrent duplication events-all containing the dosagesensitive RAI1 gene-have been observed in PTLS.…”

Objective measures of sleep disturbances in children with Potocki–Lupski syndrome

“…Potocki–Lupski syndrome (PTLS; MIM 610883) is usually associated with duplication 17p11.2 and represents a neurodevelopmental disorder characterized by infantile hypotonia, failure to thrive, congenital cardiovascular anomalies, developmental delay, intellectual disability, and behavioral abnormalities including attention deficits and features of autism spectrum disorder (Jefferies et al, ; Potocki et al, ; Potocki et al, ; Soler‐Alfonso et al, ; Treadwell‐Deering, Powell, & Potocki, ) Clinically recognizable distinct craniofacial features are usually mild in individuals with PTLS, and often include a triangular shaped face, down‐slanting palpebral fissures and mandibular hypoplasia (Neira‐Fresneda & Potocki, ; Potocki et al, ). Most subjects reported with PTLS harbor a common, recurrent duplication of 3.7 Mb within 17p11.2 that occurs de novo in association with the sporadic disease trait; however, both smaller and larger duplication copy number variants of this region will cause the PTLS phenotype (Zhang et al, ).…”

“…The common PTLS duplication and the common SMS deletion are reciprocal recombination products (Chen et al, ; Liu et al, ; Potocki, Chen, et al, ). Interestingly, these two disorders exhibit many clinical features that are on opposite ends of a given spectrum—so called “mirror traits” (Lupski, ; Neira‐Fresneda & Potocki, ). The duplicated segment in YUHAL syndrome spans not only the PTLS region, but the CMT1A (MIM 118220) region as well, thus these individuals have a more severe neuromuscular phenotype and manifest clinical signs of distal symmetric polyneuropathy observed in Charcot–Marie–Tooth disease (Yuan et al, ).…”