Refining the phenotypic spectrum of CCDC88A-related PEHO-like syndrome
Mahmoud Y Issa1, Mona A Hafez2, Samir M Mounir3
1Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Insights
Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) is a rare infantile disorder. This study identifies a new CCDC88A gene variant in an Egyptian family, expanding the known genetic causes of PEHO-like syndromes.
Area of Science:
- Genetics
- Neurology
- Rare Diseases
Background:
- Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) and PEHO-like syndromes are rare infantile disorders.
- CCDC88A is a known causative gene for PEHO and PEHO-like syndromes, with only five patients previously reported.
- These syndromes are characterized by severe intellectual disability, hypotonia, seizures, optic atrophy, and progressive brain atrophy.
Purpose of the Study:
- To report a new family with a lethal epileptic encephalopathy caused by a CCDC88A variant.
- To further delineate the phenotypic spectrum associated with biallelic loss-of-function variants in CCDC88A.
- To contribute to the understanding of the genetic basis of rare infantile neurodevelopmental disorders.
Main Methods:
- Clinical evaluation of a new patient presenting with microcephaly, poor visual responsiveness, and epilepsy.
- Brain MRI to assess neuroanatomical abnormalities.
- Whole exome sequencing to identify the genetic variant.
- Literature review of previously reported CCDC88A-associated cases.
Main Results:
- A new Egyptian family with a lethal epileptic encephalopathy was identified.
- The patient presented with microcephaly, visual impairment, epilepsy, and significant brain abnormalities including abnormal cortical gyration and reduced white matter.
- Whole exome sequencing revealed a novel homozygous frameshift variant in the CCDC88A gene (c.1795_1798delACAA, p.Thr599ValfsTer4).
- This represents the third reported family with CCDC88A-associated PEHO-like disorder.
Conclusions:
- This study describes a novel homozygous CCDC88A variant in a consanguineous Egyptian family, presenting a severe epileptic encephalopathy.
- The findings expand the spectrum of CCDC88A-related disorders and highlight its role in infantile neurodevelopment.
- Further research is needed to fully understand the pathogenicity and clinical implications of CCDC88A variants.
Abstract:
Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) and PEHO-like syndromes are very rare infantile disorders characterized by profound intellectual disability, hypotonia, convulsions, optic, and progressive brain atrophy. Many causative genes for PEHO and PEHO-like syndromes have been identified including CCDC88A. So far, only five patients from two unrelated families with biallelic CCDC88A variants have been reported in the literature. Herein, we describe a new family from Egypt with a lethal epileptic encephalopathy. Our patient was the youngest child born to a highly consanguineous couple and had a family history of five deceased sibs with the same condition. She presented with postnatal microcephaly, poor visual responsiveness, and epilepsy. Her brain MRI showed abnormal cortical gyration with failure of opercularization of the insula, hypogenesis of corpus callosum, colpocephaly, reduced white matter, hypoplastic vermis, and brain stem. Whole exome sequencing identified a new homozygous frameshift variant in CCDC88A gene (c.1795_1798delACAA, p.Thr599ValfsTer4). Our study presents the third reported family with this extremely rare disorder. We also reviewed all described cases to better refine the phenotypic spectrum associated with biallelic loss of function variants in the CCDC88A gene.
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