Whole gene duplication of the PQBP1 gene in syndrome resembling Renpenning

Abstract

Renpenning syndrome is a well-described X-linked condition associated with multiple congenital anomalies and intellectual disability [OMIM 309500]. Typical signs include microcephaly, dysmorphic features, short stature, small testes, and lean body build. Renpenning syndrome is caused by mutations in the polyglutamine binding protein 1 (PQBP1) gene. Missense mutations, insertions, deletions, and duplications within the gene have been well-described. We present a 47-year-old male with clinical features resembling Renpenning syndrome. He has moderate intellectual disability, seizures since infancy, short stature, small testes, and dysmorphic features. Of note, our patient is normocephalic. A CT scan at 14 years of age showed cerebral atrophy. He had previously been verbally communicative and had few behavioral issues. Recently, our patient has regressed and has become uncommunicative, displaying little and unclear speech. He now exhibits memory and recognition loss and is uncooperative, aggressive, self-abusive, and incontinent. The reason for his regression within the past 4 years is unclear. SNP microarray analysis (500K) revealed a 4.7 Mb duplication at Xp11.22-p11.23. Multiple ligation probe amplification (MLPA) of the PQBP1 gene contained within this duplicated region confirmed a duplication of the entire PQBP1 gene. Multiple other genes are duplicated within this 4.7 Mb region and may contribute to his phenotype.

The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling

“…Overexpression of PQBP1 is also deleterious, promoting neuronal cell death in mice (Okuda et al, 2003;Marubuchi et al, 2005), and impaired long-term memory and behavioral abnormalities in Drosophila (Yoshimura et al, 2006). A PQBP1 gene duplication has been found in a patient with Renpenning syndrome, in which the PQBP1 protein may be overexpressed (Flynn et al, 2011). All of these findings suggest that maintaining PQBP1 within a restricted concentration range is essential for its proper biological actions.…”

Xp11.2 Duplication in Females: Unique Features of a Rare Copy Number Variation

“…We observed it in Patients 1 and 3, especially in the field of motor skills. In a male patient with recurrent Xp11.22p11.23 duplication, Flynn et al (2011) described regression in areas of speech, memory and recognition, furthermore, leading to aggressive behavior. Helm et al (2017) reported regression of development with co-occurrence of the onset of seizures in a 20 year-old male patient.…”

“…Non-recurrent duplications of 0, 3-55 Mb in size have been reported in addition to the recurrent form of about 4.5 Mb, therefore the genes involved in the individual patient's duplications may be quite different. Patients with this copy number alteration, which have become known so far, show surprisingly similar symptoms despite the variability in CNV size: the resulting symptoms do not correlate with size and gene content of the affected genomic regions (Giorda et al, 2009;Zou and Milunsky, 2009;Flynn et al, 2011;Arican et al, 2018).…”

“…The duplication affecting the Xp11.23p11.22 region is unique even among these specific CNVs of X chromosome. It is very rare occurring in both genders (Kokalj Vokac et al, 2002;Bonnet et al, 2006;Froyen et al, 2008Froyen et al, , 2012Monnot et al, 2008;Giorda et al, 2009;Zou and Milunsky, 2009;Holden et al, 2010;Honda et al, 2010;Broli et al, 2011;Chung et al, 2011;Edens et al, 2011;El-Hattab et al, 2011;Flynn et al, 2011;Nizon et al, 2014;Evers et al, 2015;Grams et al, 2015;Moey et al, 2016;Orivoli et al, 2016;Arican et al, 2018;Wang et al, 2020). Inherited and de novo forms are known, all de novo Xp11.23 duplications in which parent of origin has been determined have been paternally inherited (Deng et al, 1990).…”

PQBP1: The Key to Intellectual Disability, Neurodegenerative Diseases, and Innate Immunity

“…Flynn et al reported duplication of the PQBP1 gene and a phenotype-like Renpenning’s syndrome in a patient [ 72 ]. SNP microarray analysis (500 K) of the patient showed a 4.7 Mb duplication at Xp11.22–p11.23, including the PQBP1 gene, which was further confirmed to be duplicated using Multiplex Ligation-dependent Probe Amplification (MLPA) [ 67 ].…”