Korzun PR, Binnatova JO, Malysheva KS, Laptiev SA, Abuzova AS, Kipyatkova AO, Kuznetsova OA, Yefet EA, Malekov DA, Imyanitov EN, Suspitsin EN. Combined homozygous HACE1 and TBCD variants in two siblings with severe early-onset neurodevelopmental disorder: Two case reports. World J Clin Cases 2026; 14(19): 120750 [DOI: 10.12998/wjcc.120750]
Corresponding Author of This Article
Evgeny N Suspitsin, MD, PhD, Department of Medical Genetics, St. Petersburg State Pediatric Medical University, Litovskaya St., 2, St. Petersburg 194100, Russia. evgeny.suspitsin@gmail.com
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Genetics & Heredity
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case-report
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Korzun PR, Binnatova JO, Malysheva KS, Laptiev SA, Abuzova AS, Kipyatkova AO, Kuznetsova OA, Yefet EA, Malekov DA, Imyanitov EN, Suspitsin EN. Combined homozygous HACE1 and TBCD variants in two siblings with severe early-onset neurodevelopmental disorder: Two case reports. World J Clin Cases 2026; 14(19): 120750 [DOI: 10.12998/wjcc.120750]
World J Clin Cases. Jul 6, 2026; 14(19): 120750 Published online Jul 6, 2026. doi: 10.12998/wjcc.120750
Combined homozygous HACE1 and TBCD variants in two siblings with severe early-onset neurodevelopmental disorder: Two case reports
Polina R Korzun, Jeyla O Binnatova, Kristina S Malysheva, Sergey A Laptiev, Anastasiya S Abuzova, Anastasiya O Kipyatkova, Olga A Kuznetsova, Elena A Yefet, Damir A Malekov, Evgeny N Imyanitov, Evgeny N Suspitsin
Polina R Korzun, Jeyla O Binnatova, Kristina S Malysheva, Sergey A Laptiev, Anastasiya S Abuzova, Anastasiya O Kipyatkova, Evgeny N Imyanitov, Evgeny N Suspitsin, Department of Medical Genetics, St. Petersburg State Pediatric Medical University, St. Petersburg 194100, Russia
Olga A Kuznetsova, Elena A Yefet, Department of Psychoneurology, St. Petersburg State Pediatric Medical University, St. Petersburg 194100, Russia
Damir A Malekov, Department of Radiology, St. Petersburg State Pediatric Medical University, St. Petersburg 194100, Russia
Evgeny N Imyanitov, Evgeny N Suspitsin, Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg 197758, Russia
Author contributions: Korzun PR and Malysheva KS designed the research study; Laptiev SA and Abuzova AS analyzed medical histories; Kuznetsova OA, Yefet EA, and Malekov DA monitored and treated the patients; Korzun PR and Binnatova JO performed the genetic testing; Kipyatkova AO contributed to bioinformatics pipelines; Suspitsin EN and Imyanitov EN wrote the manuscript; All authors approved the final version of the article.
AI contribution statement: AI tools (specifically Gemini) were used solely for linguistic refinement and formatting assistance. No AI tool was involved in the generation of research data, interpretation of results, or formulation of conclusions. All AI-generated outputs were critically reviewed and revised by the authors.
Supported by Russian Science Foundation, No. 24-45-00067.
Informed consent statement: Written informed consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Corresponding author: Evgeny N Suspitsin, MD, PhD, Department of Medical Genetics, St. Petersburg State Pediatric Medical University, Litovskaya St., 2, St. Petersburg 194100, Russia. evgeny.suspitsin@gmail.com
Received: March 9, 2026 Revised: May 12, 2026 Accepted: May 27, 2026 Published online: July 6, 2026 Processing time: 117 Days and 2.7 Hours
Abstract
BACKGROUND
Spastic paraplegia and psychomotor retardation with or without seizures (spastic paraplegia and psychomotor retardation with or without seizures; MIM #616756) is a rare autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants in HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) gene. Mutations in the tubulin-specific chaperone D (TBCD) gene cause progressive early-onset encephalopathy with brain atrophy and a thin corpus callosum (PEBAT; MIM #617193). Approximately 40 cases are documented for each disorder. Despite different mechanisms, HACE1- and TBCD-associated disorders share overlapping features, complicating early differential diagnosis. We report co-occurrence of homozygous variants in HACE1 and TBCD in two brothers with global developmental delay.
CASE SUMMARY
We describe two Chechen brothers born to healthy unrelated parents. The older brother (3 years 10 months) presented with profound global developmental delay, mixed tetraparesis, early-onset epileptic encephalopathy, generalized epilepsy, dysphagia, and protein-energy malnutrition. Brain magnetic resonance imaging revealed marked cerebral/cerebellar atrophy, corpus callosum hypoplasia, gliosis and cystic frontoparietal changes. The younger brother (2 years 2 months) exhibited ataxic cerebral palsy, severe developmental delay, and recurrent febrile episodes. Neuroimaging demonstrated corpus callosum hypoplasia, mild periventricular white matter T2-fluid-attenuated inversion recovery (T2-FLAIR) signal hyperintensities, and compensatory (ex vacuo) enlargement of both ventricles and subarachnoid spaces. Whole-exome sequencing performed in the younger brother identified homozygous truncating HACE1 c.625C>T (p.Gln209*) and a novel homozygous missense TBCD c.2139T>A (p.His713Gln) variants. The older brother shared both homozygous variants; parents were asymptomatic carriers. Although the TBCD variant initially appeared likely pathogenic, in silico predictions and its frequency in the Chechen population led to a likely benign classification, though a potential modifying effect on the disease course cannot be excluded.
CONCLUSION
This family represents combined homozygous HACE1 and TBCD variants in two siblings with severe neurodevelopmental impairment. HACE1 causes the phenotype, while TBCD is likely a neutral ethnicity-specific allele.
Core Tip: This report describes two brothers sharing homozygous variants in HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) and tubulin-specific chaperone D (TBCD) genes. Both siblings have severe developmental delay, spastic tetraparesis, early-onset epileptic encephalopathy, and marked cerebral and cerebellar atrophy with corpus callosum hypoplasia, highlighting the challenges of diagnosing overlapping neurogenetic syndromes. Exome testing revealed that they both share the truncating HACE1 c.625C>T variant that explains their clinical symptoms. Conversely, a novel TBCD c.2139T>A allele is likely benign, illustrating the importance of population-specific genetic datasets.
