UNC80 Deficiency Due to a Novel Homozygous Deletion: A Case Report
Devi Saranya S *1, Nikitha Rafeek 2, Darshan Jayaram Das 2, Belvina Ann Joseph 3, Anu Davis 1
*Correspondence to: Devi Saranya S. Consultant Medical Genetics, Rajagiri Hospital, Kochi, Kerala, India- 683112.
Copyright
© 2026: Devi Saranya S. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 31 August 2026
Published: 01 October 2026
DOI: https://doi.org/10.5281/zenodo.23180192
Introduction
UNC80 deficiency is a rare autosomal recessive neurodevelopmental disorder characterized by severe global developmental delay, epilepsy, hypotonia, dyskinesia, and distinctive facial features. UNC80 encodes a critical component of the sodium leak channel complex which regulates neuronal excitability. Pathogenic variants are predominantly point mutations, copy number variations being rare.
Case Presentation
We report a 3-year-9-month-old Indian boy, born to consanguineous parents, presenting with severe global developmental delay, drug refractory epilepsy, severe hypotonia, intermittent convergent squint, dysmorphism, dyskinetic movements, and chronic refractory constipation. Neuroimaging showed mild diffuse parenchymal atrophy; electroencephalography demonstrated multifocal epileptiform abnormalities. Exome sequencing identified a novel homozygous 24 kb exon 7 deletion in the UNC80 gene, resulting in complete loss-of-function. This is the first reported Indian case of UNC80 deficiency and shows striking phenotypic concordance with previously described cases.
Conclusion
The mutational spectrum has predominantly comprised point mutations; copy number variants are rare, with only one previously reported case. Our patient expands this spectrum by describing a novel homozygous single exon deletion. This case highlights the importance of comprehensive genetic testing in undiagnosed neurodevelopmental disorders, particularly in the context of consanguinity and suggestive phenotypic features. Early molecular diagnosis enables accurate prognostication, appropriate management, and genetic counseling for affected families.
Keywords: UNC80 deficiency, neurodevelopmental disorder, copy number variant, epileptic encephalopathy, Exome sequencing
Introduction
UNC80 deficiency is an autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants in the UNC80 gene, classified as infantile hypotonia with psychomotor retardation and characteristic facies type 2 [OMIM: #61684] [1, 2]. The clinical phenotype is characterized by profound infantile hypotonia presenting from birth, severe global developmental delay with absent ambulation and speech, and intellectual disability [1,2,3]. Epilepsy occurs in a significant proportion of patients during early childhood, accompanied by involuntary movements in the majority of cases [3,4,5]. Other systemic manifestations include postnatal growth deficiency, strabismus, and chronic constipation, with nonspecific dysmorphic features such as thin upper lip and triangular face [1,2,3].
The UNC80 gene encodes a critical component of the sodium leak channel complex, which regulates resting membrane potential and neuronal excitability [4]. The UNC80 protein serves as a structural bridge between the pore-forming NALCN subunit and the UNC79 protein, and is essential for channel stability and function [1,4]. Biallelic loss-of-function mutations disrupt this complex, impairing sodium leak currents and altering neuronal excitability [1,4]. Mutations in the related gene, NALCN cause overlapping phenotypes including infantile hypotonia with psychomotor retardation and characteristic facies type 1 [OMIM: #615419] and Congenital contractures of the limbs and face, hypotonia, and developmental delay [OMIM: #616266] [4].
The mutational spectrum predominantly consists of nonsense, frameshift, and splice-site variants causing loss of function [1,2,3,6]. Copy number variations in this gene are rare and only a single case of multi-exonic deletion has been reported in this gene till date [7]. While cases have been described in European, Arab, Chinese, Thai and Turkish populations, there are no previously reported cases from India [1,2,3,8]
Here, we report the first Indian case of epileptic encephalopathy due to a novel biallelic deletion in the UNC80 gene, expanding the mutational spectrum and highlighting the importance of genetic testing in undiagnosed epilepsy syndromes.
Case Report
A 3-year-9-month-old male child, the first-born of non-affected parents in a third-degree consanguineous marriage, presented with profound global developmental delay and refractory epilepsy. The pregnancy was complicated by severe oligohydramnios, and the child was delivered at term by cesarean section. Birth weight was 2.9 kilograms, and the child cried immediately after birth with no requirement for neonatal intensive care admission. Neonatal jaundice requiring phototherapy was noted in the postnatal period. Family history was significant for a maternal sibling affected by undiagnosed disorder characterized by neural tube defect and early infantile death.
Severe neurodevelopmental impairment was evident from early infancy. The child attained neck holding and rolling over by 2.5 years and currently, at 3 years 9 months of age, sits with support. He remains non-verbal and recognizes her parents. Significant feeding difficulty and chronic refractory constipation has been present since birth, indicating severe oral-motor incoordination.
Physical examination revealed plagiocephaly, hypotelorism, prominent nasal bridge, thin lips, open mouth appearance, and short philtrum, consistent with characteristic facies (Figure 1). Hands and feet were normal. Severe generalized hypotonia was present, most pronounced in the trunk. Ophthalmic evaluation demonstrated intermittent convergent squint. Neurological examination additionally revealed dyskinetic movements involving the limbs. Ultrasound abdomen performed was normal.
The child has a developmental and epileptic encephalopathy phenotype with history of refractory epilepsy, initially presenting as infantile spasms. The seizure disorder has since evolved and is currently managed with a combination of anti-epileptic drugs. Despite treatment, the child continues to experience daily episodes of axial tonic seizures characterized by uprolling of eyes with unresponsiveness and slow head drops lasting for a few seconds.
Electroencephalogram demonstrated multifocal epileptiform abnormalities along with mild degree of generalized non-specific disturbances of electrical function. Magnetic resonance imaging of the brain revealed mild diffuse parenchymal atrophy, a non-specific but common finding in early-onset neurodevelopmental disorders.
Given the presence of global developmental delay, hypotonia, infantile spasms, dyskinesias, characteristic facies, chronic constipation, and significant family history of consanguinity with an affected maternal sibling, a genetic etiology was strongly suspected. Exome sequencing was performed to investigate the underlying cause.
Exome sequencing identified a homozygous likely pathogenic deletion in the UNC80 gene. The UNC80 gene comprises 64 exons. The homozygous structural variant NC_000002.12. (209789606_209793719)_(209793860_209813579) del (GRCh38, chromosome 2), encompassing exon 7 of UNC80 (ENST00000673920.1), with breakpoints located within the flanking introns, and was predicted to result in loss of function. The phenotype of hypotonia, infantile spasms, developmental delay, and characteristic facies showed strong concordance with UNC80-related disorder. Chromosomal microarray analysis and parental segregation analysis would be the optimal next test to precisely define the deletion boundaries and exon-level resolution; however, this could not be performed due to financial constraints.
Current management is supportive and multidisciplinary, including feeding support, physiotherapy, anti-seizure medications and regular neurological follow-up. The child remains dependent for most motor and daily living skills, consistent with the severe phenotype of UNC80 deficiency.
Discussion
The clinical phenotype in our patient shows a good concordance with previously described cases of UNC80 deficiency. The core features of profound infantile hypotonia, severe global developmental delay, and characteristic facies (thin upper lip, triangular face, short philtrum) align precisely with the literature [1,2]. The inability to achieve independent ambulation or expressive speech reflects the severe end of the neurodevelopmental spectrum reported in most cases [4, 6].
Epilepsy occurs in approximately seventy percent of patients with loss-of-function variants and is refractory to treatment in nearly sixty percent of cases [5]. Our patient's presentation with infantile spasms evolving into daily axial tonic seizures is consistent with this reported phenotype. Systemic manifestations also mirror the expanding phenotypic spectrum. Severe chronic refractory constipation, poorly responsive to oral laxatives, aligns with reports of gastrointestinal involvement [4]. Feeding difficulties since birth likely reflect significant oral–motor incoordination, while the intermittent convergent squint is in keeping with the strabismus frequently described in UNC80 deficiency [1,2]. The presence of dyskinetic movements are also significant [6].
The mutational landscape of UNC80-related disorders has predominantly consisted of point mutations including nonsense, frameshift, and splice-site variants resulting in loss of function [1,2,4,6]. These mutations are distributed throughout the gene without evidence of genotype-phenotype correlation, suggesting that complete loss of function produces a consistent severe phenotype [4]. However, a very recent report has expanded this spectrum by describing a novel intragenic deletion involving five exons in an Italian family, demonstrating that copy number variants can also cause this disorder [7]. Our patient harbours a novel homozygous deletion spanning approximately 24 kilobases and involving exon 7. This represents the first reported case from India and further expands the copy number variant spectrum of UNC80-related disorders. Given that the UNC80 protein serves as an essential component of the NALCN channel complex regulating neuronal excitability, this single exonic deletion would abolish UNC80 expression entirely, leading to disrupted channel function.
This case highlights the importance of maintaining a high index of suspicion for genetic etiologies in children presenting with severe neurodevelopmental impairment, particularly in the context of consanguinity in the family history. The presence of characteristic facial features, dyskinesia, refractory epilepsy, and multisystem involvement should prompt genetic investigation rather than defaulting to a diagnosis of cerebral palsy [5,8,9]. Early molecular diagnosis enables appropriate management, prognostication, and genetic counseling for families.
Furthermore, this case highlights the importance of comprehensive genetic testing approaches. Without dedicated analysis for copy number variants, structural abnormalities such as the deletion identified in our patient can be missed on routine exome sequencing. A combined approach using both exome sequencing and chromosomal microarray analysis optimizes diagnostic yield in such cases, as demonstrated by the recent Italian report [7].
Conclusion
We report the first Indian case of UNC80 deficiency due to a novel homozygous exon 7 deletion, expanding the mutational spectrum to include copy number variants and highlighting the importance of comprehensive genetic testing in undiagnosed neurodevelopmental disorders.
Statements
Acknowledgments:
We acknowledge patient and family for their consent and cooperation.
Statement of Ethics
Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying clinical details. According to the institutional policy, ethical committee approval is not required for single case reports.
Conflict of Interest Statement:
The authors have no conflicts of interest to declare.
Funding Sources: None.
Author Contributions: DSS: Conceptualization of the study, patient management, manuscript writing, and critical review.NR, DJD, AD: Patient management and manuscript review. BAJ: Manuscript writing.
Data Availability Statement
Data will be available on request to the corresponding author.
References