Phenotypic and molecular insights into PQBP1‐related intellectual disability

Abstract

We report two discordant clinical and imaging features in four male patients from two unrelated families of Egyptian descent with hemizygous pathogenic variants in PQBP1. The three patients of the first family displayed the typical features underlying PQBP1 such as the long triangular face, bulbous nose, hypoplastic malar region, and micrognathia, which were subsequently confirmed using targeted sequence analysis that showed a previously reported nonsense mutation c.586C>T p.R196*. Whole exome sequencing identified a novel missense PQBP1 variant c.530G>A:p.R177H in the second family, in which the index patient presented with intellectual disability and dysmorphic facial features reminiscent of Kabuki‐like syndrome and his brain magnetic resonance imaging revealed partial agenesis of corpus callosum, mild vermis, and brainstem hypoplasia. These imaging features are distinct from the previously described with a well‐known phenotype that is already known for PQBP1. This report expands the phenotypic spectrum of PQBP1‐related disorders and is the second reported missense PQBP1 variant. Further, it highlights the possible role of PQBP1 in hindbrain development.

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

“…A study on Qatari subjects revealed the association of a novel pathogenic PGAP3 variant with global developmental delay and neuromuscular abnormalities and brain anomalies [ 45 ]. Studies on Egyptian subjects revealed the association of pathogenic SCN10A variation in patients with neuromuscular disease and epileptic encephalopathy [ 46 ], SLC39A8 variation in patients with intellectual disability, developmental delay, cerebellar atrophy, hypotonia, strabismus, and variable short stature [ 47 ], PQBP1 variation in patients with intellectual disability [ 48 ] biotin-thiamine responsive encephalopathy [ 49 ] and TTC5 variation in patients with intellectual disability syndromes [ 50 ]. The PUS3 gene with a frameshift variant was observed as a candidate gene for intellectual disability in a study with 103 families from Jordan [ 51 ].…”

Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome

“…In humans, most of the variants described are small indels, located in the AG hexamer of exon 4 or downstream, resulting in truncated proteins lacking their C-terminal domain, but few additional truncating variants were also reported (6,(20)(21)(22). Only few missense variants have been reported in PQBP1 and for years, only a unique missense variant (p.Tyr65Cys) was considered as pathogenic (4).…”

A rigorous in silico genomic interrogation at 1p13.3 reveals 16 autosomal dominant candidate genes in syndromic neurodevelopmental disorders

“…AHDC1 (Marcon et al, 2014): syndromic expressive language delay, hypotonia & sleep apnoea (Xia et al, 2014), Xia-Gibbs syndrome (Garcia-Acero and Acosta, 2017; Jiang et al, 2018;Wang et al, 2020;Faergeman et al, 2021), neurodevelopmental disorder (Wang et al, 2020), intellectual disability and developmental delay (Yang et al, 2015;Pekeles et al, 2019), autism spectrum disorder (Iossifov et al, 2014;Kosmicki et al, 2017;Lim et al, 2017), moderate intellectual disability, speech delay, macrocephaly, facial dysmorphism, cleft palate, hypertelorism & macrocrania (Bowling et al, 2017;Jiang et al, 2018) 5. PQBP1 (Stelzl et al, 2005): mental retardation (Kalscheuer et al, 2003;Lenski et al, 2004;Jensen et al, 2011;Rahman et al, 2019), intellectual disability (Redin et al, 2014;Grozeva et al, 2015;Hu et al, 2016;Abdel-Salam et al, 2018), microcephaly (Shaheen et al, 2019) 6. SETD1B (Goehler et al, 2004): intellectual disability and seizures (Brunet et al, 2021;Roston et al, 2021), Intellectual disability, developmental delay, epilepsy, language disorder, autism, facial dysmorphism (Palumbo et al, 2015;Faundes et al, 2018;Hiraide et al, 2018Hiraide et al, , 2019Hiraide et al, , 2021, autism spectrum disorder (Iossifov et al, 2014;Satterstrom et al, 2020), Developmental and epileptic encephalopathy (Takata et al, 2019), schizophrenia (Wang et al, 2015...…”

“…PQBP1 ( Stelzl et al, 2005 ): mental retardation ( Kalscheuer et al, 2003 ; Lenski et al, 2004 ; Jensen et al, 2011 ; Rahman et al, 2019 ), intellectual disability ( Redin et al, 2014 ; Grozeva et al, 2015 ; Hu et al, 2016 ; Abdel-Salam et al, 2018 ), microcephaly ( Shaheen et al, 2019 )…”