PGAP3‐related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation

Abstract

Background Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by recessive mutations in genes involved in the glycosylphosphatidylinsitol pathway, including PGAP3. Materials and Methods We describe 10 patients from 8 Egyptian families presenting with developmental delay, severe intellectual disability, distinct facial dysmorphism and increased alkaline phosphatase. Sanger sequencing of PGAP3 was performed. Results Eight patients had cleft palate, 4 had postnatal microcephaly and 5 had seizures. Neuro‐imaging findings showed thin corpus callosum in 9 patients, mild ventriculomegaly in 3 patients and variable degrees of cerebellar vermis hypoplasia in 4 patients, a finding not previously reported in patients with HPMRS. Additional manifestations included double row teeth, hypogenitalism and congenital heart disease. Biallelic loss of function mutations in the PGAP3 gene were detected in all patients. Nine patients were homozygous for the c.402dupC (p.M135Hfs*28) mutation strongly suggesting a founder effect. On the other hand, 1 patient had a novel mutation, c.817_820delGACT (p.D273Sfs*37). Conclusion This is the largest series of patients with HPMRS from same ethnic group. Our results reinforce the distinct clinical and facial features of PGAP3‐related HPMRS which are the clue for targeted genetic testing. Moreover, we present additional unreported clinical and neuro‐imaging findings and a novel mutation thus expanding the phenotypic and mutational spectrum of this rare disorder.

Characterization of Glycosylphosphatidylinositol Biosynthesis Defects by Clinical Features, Flow Cytometry, and Automated Image Analysis

“…The craniofacial characteristics of many Mendelian disorders are highly informative for clinical geneticists and have also been used to delineate gene-specific phenotypes of several GPIBDs [3-5, 10, 19, 27-29, 31, 38, 39, 43, 44, 59-61]. However, our medical terminology is often not capable of describing subtle differences in the facial gestalt.…”

“…We used the RESEARCH app of the Face2Gene suite to evaluate a classifier for the five most prevalent GPIBDs, that is PIGA (n=20), PIGN (n=11), PIGT (n=12), PIGV (n=25), and PGAP3 (n=23) at the current moment. Our original sample set thus consists of frontal facial photos of 91 individuals with a molecularly confirmed diagnosis of HPMRS or MCAHS, including cases that have been previously published [5, 9-11, 13-15, 19, 27-29, 31-33, 38, 43, 47, 49, 50, 52-56, 60, 63]. The mean accuracy that is achieved on this original sample set is 52.2 %, which is significantly better than randomly expected.…”

“…We therefore evaluated the area under the receiver operating characteristics curve (AUC) and found the correct gene-p rediction more often than randomly expected, including PIGV versus PGAP3 (Figure S3). The differences in pair-wise comparison between PIGV and PGAP3 could be confounded by the large number of Egyptian cases in the PGAP3 cohort [38], the effect of which we could not further analyze due to the limited set of patients photos.…”

“…Psychomotor delay, ID and variable AP elevation are the only consistent features of all individuals with pathogenic mutations in PIGV [9, 27-33], PIGO [7, 16, 17, 30, 34-36], PGAP2 [4, 8, 18, 37], PGAP3 [5, 19, 38-40], PIGW [3, 41], and PIGY [6]. Speech development, especially expressive language, is more severely affected than motor skills in the majority of the affected individuals (Table S1).…”

“…Cleft palate is the malformation with the highest frequency in the group of affected individuals with PGAP3 mutations with a prevalence of almost 60%, whereas other malformations are rarely observed. Exceptional is a group of 10 Egyptian individuals with the same founder mutation and a high incidence of structural brain anomalies (thin corpus callosum (8/10), vermis hypoplasia (4/10), ventriculomegaly (3/10) and Dandy-Walker malformation (1/10) [28, 38]. Up to date these are the few individuals with a presumable complete loss of function for this gene (NM_033419.3:c.402dupC, p.Met135Hisfs*28; c.817_820 delGACT, p.Asp273Serfs*37)).…”