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


Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by recessive mutations in genes involved in the glycosylphosphatidylinsitol pathway, including PGAP3. Herein, we describe 10 patients from 8 Egyptian families presenting with developmental delay, severe intellectual disability, distinct facial dysmorphism and increased alkaline phosphatase. Eight patients had cleft palate, four had postnatal microcephaly and five had seizures. Neuroimaging 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, one patient had a novel mutation, c.817_820delGACT (p.D273Sfs*37). To our knowledge, 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.

Graphical abstract

We describe 10 patients from 8 unrelated Egyptian families with PGAP3‐related HPMRS and expand the associated phenotypic and mutational spectrum.

We report for the first time that biallelic loss of the function mutations in PGAP3 gene could be associated with the severe end of clinical spectrum of this rare disorder in humans.

Authors:   M.S. Abdel‐Hamid, M.Y. Issa, G.A Otaify, S.F. Abdel‐Ghafar, H.M. Elbendary, M.S. Zaki
Journal:   Clinical Genetics
Year:   2017
Pages:   n/a
DOI:   10.1111/cge.13033
Publication date:   08-Apr-2017
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