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Abstract Details

Expanding the Clinical Spectrum of NUBPL Associated Disorders: Previously Unidentified NUBPL Variants Uncovered by Genome Sequencing in Sibling Pair
Child Neurology and Developmental Neurology
P10 - Poster Session 10 (5:00 PM-6:00 PM)
6-009

We present a case of two siblings exhibiting variable clinical phenotypes despite sharing the same variants in the NUBPLgene. This case aims to explore the genotype-phenotype correlations and the implications of genetic testing in diagnosing mitochondrial disorders. 

Mitochondrial respiratory chain complex I is encoded by multiple nuclear and mitochondrial genes, including NUBPL. Biallelic pathogenic variants in NUBPL are associated with broad developmental and neurological findings and variable MRI patterns. 
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A 6-year-old female with a history of ataxia, global developmental delay, and hypermobility developed acute regression following a respiratory illness at 4 years old (Leigh syndrome). Her MRI showed a frontally predominant leukodystrophy and cerebellar atrophy. Biochemical testing was within normal limits, including urine organic acids, plasma acylcarnitine profile, plasma amino acids, and lactate. Her 15-year-old brother presented with global developmental delay with less severe and later onset motor delays, nystagmus, tremors, spasticity, and ataxia. His MRI showed diffuse leukoencephalopathy involving the corpus callosum and brainstem with extensive cerebellar atrophy. His MR spectroscopy demonstrated a lactate peak, CSF showed an elevated lactate level, and his muscle biopsy depicted complex I deficiency. Prior exome sequencing and mtDNA sequencing (blood and buccal swab) for both siblings were unrevealing. However, whole genome sequencing revealed biallelic variants in NUBPL. Both siblings harbored a maternally inherited complex allele involving the heterozygous variant c.166G>A (p.Gly56Arg) and a hemizygous variant c.815-27T>C, in cis configuration. They also carry an in trans paternally inherited heterozygous deletion encompassing exon 10 of NUBPL.

NUBPL variants can present with variable clinical phenotypes and MRI patterns even among first-degree siblings. Expanding genetic workup to include whole genome sequencing should be considered when suspecting mitochondrial disease with negative exome and mtDNA sequencing. Further research is needed to elucidate the mechanisms underlying these phenotypic variabilities.
Authors/Disclosures
Shadi Shams
PRESENTER 		Dr. Shams has nothing to disclose.
Shahad Olsson, CGC Mrs. Olsson has nothing to disclose.
Sophia Ceulemans, MS, CGC Ms. Ceulemans has a non-compensated relationship as a Member of Professional Advisory Board with Epilepsy Foundation of San Diego that is relevant to AAN interests or activities.
Diana Alzate, LCGC Ms. Alzate has nothing to disclose.
Lucia Guidugli, PhD Dr. Guidugli has nothing to disclose.
Jennifer H. Yang, MD (Rady Childrens Hospital/UCSD) Dr. Yang has received research support from Pediatric Epilepsy Research Foundation. Dr. Yang has received research support from NIH.