RAI1 – Potocki-Lupski syndrome

Potocki-Lupski syndrome (MONDO:0012574) is an autosomal dominant neurodevelopmental disorder caused by microduplication of the 17p11.2 region, with dosage gain of the RAI1 gene central to pathogenesis. Affected individuals typically present with infantile hypotonia, mild intellectual disability, failure to thrive, and subtle craniofacial dysmorphism.

A 3-year-old boy with the smallest reported 0.25 Mb 17p11.2 duplication including RAI1 exhibited mild intellectual disability (IQ 65), dolichocephaly (HP:0000268), flat feet (HP:0001763), and language delay without autistic features or internal organ anomalies (PMID:23078968).

A separate patient presented with hypoplastic left heart (HP:0004383), severe feeding difficulties (HP:0011968), failure to thrive (HP:0001508), hypotonia (HP:0001252), and global developmental delay (HP:0001263), highlighting the variability of cardiovascular involvement; diagnosis was confirmed by array CGH at age 4 (PMID:21271655).

In an 8-patient cohort, all individuals displayed infantile muscular hypotonia (HP:0008947) and mild to moderate cognitive impairment; autism spectrum features and sleep disturbances were variably present, whereas hypotonia was less frequent than earlier reports (PMID:33043631).

Functional studies demonstrate that graded overexpression of Rai1 in mouse models yields growth retardation, hyperactivity, anxiety-related behavior, and neuromotor deficits in a dose-dependent manner (PMID:18285828). Moreover, structural variants upstream of RAI1 alter cis-regulatory elements and elevate RAI1 mRNA levels, confirming dosage sensitivity and supporting diagnostic interpretation of non-coding CNVs (PMID:26442755).

Collectively, these data establish a Strong gene–disease association: de novo 17p11.2 microduplications encompassing RAI1 in ~10 probands with consistent phenotypes, supported by concordant murine overexpression models. Key take-home: RAI1 dosage gain reliably underlies PTLS, informing targeted CNV analysis and prognostic counseling.

References

• Brain & development • 2013 • Clinical and cytogenetic features of a Potocki-Lupski syndrome with the shortest 0.25Mb microduplication in 17p11.2 including RAI1. PMID:23078968
• American journal of medical genetics. Part A • 2011 • The severe end of the spectrum: Hypoplastic left heart in Potocki-Lupski syndrome. PMID:21271655
• American journal of medical genetics. Part A • 2020 • Neurological phenotype of Potocki-Lupski syndrome. PMID:33043631
• European journal of human genetics : EJHG • 2008 • How much is too much? Phenotypic consequences of Rai1 overexpression in mice. PMID:18285828
• Molecular cytogenetics • 2015 • Copy number loss upstream of RAI1 uncovers gene expression regulatory region that may impact Potocki-Lupski syndrome diagnosis. PMID:26442755

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