Patient Clinical Information: The patient is a 13 year-old female reported to have tuberous sclerosis and seizures, slowly progressive loss of milestones over the last year, increased agitation and fevers, and decreased oral intake. The patient is confined to a wheelchair and has constant writhing and spastic movements accompanied by arching and intense muscle contraction and twitching.
Family History: The patient’s mother and two siblings are affected by tuberous sclerosis, and the father passed away four years ago from what was clinically diagnosed as “Huntington” disease.
Testing Ordered: Comprehensive Spinocerebellar Ataxia Repeat Expansion Panel
Genetic Findings: Previous testing performed on this patient included HTT trinucleotide repeat analysis based on the father’s Huntington disease diagnosis, resulting in both alleles within normal range, and whole exome sequencing that found a TSC1 splice-site variant, consistent with the TSC diagnosis already known. However, through additional repeat expansions analysis, we found an expansion in the ATN1 gene, causing Dentatorubral-pallidoluysian atrophy (DRPLA). The patient had one normal-range allele of 15 repeats, and one expanded allele at 67 repeats.
Outcome: The affected range for DRPLA is 36 or more repeats, with higher numbers of repeats correlating with earlier onset of disease, and with repeats over 65 being associated with infant and childhood-onset of symptoms. This is a rare autosomal dominant spinocerebellar ataxia with an estimated incidence of 2 to 7 per million people, and is primarily found in Japanese populations.
Due to genetic anticipation, affected offspring are expected to have symptoms 26 to 29 years earlier than affected fathers and 14 to 15 years earlier than affected mothers, and a differential diagnosis for adult-onset DRPLA includes Huntington disease. The results explain the clinical presentation and early onset DRPLA in the patient, as well as the father’s previous diagnosis.
Figure 1: The top portion shows the patient’s allele profile for ATN1/DRPLA repeat expansion analysis with one allele at 15 repeats, considered normal, and the second expanded allele at 67 repeats. The bottom profile with control alleles shows what would be expected as normal repeat lengths at 9 and 15 repeats. The red line at 65 repeats shows the cut-off for early onset of Dentatorubral-pallidoluysian atrophy symptoms, consistent with the patient’s phenotype.
Reported by: Dimiter Kolev, Associate Reporting Specialist
As part of MNG Laboratories’ dedication to continued education, we are committing to a periodic Challenging Cases webinar series to complement our MNG Answers™ program. Each quarter we will present our most challenging cases and explain how advanced sequencing technologies improved the clinical sensitivity of the testing, and led to a diagnostic answer. MNG Laboratories’ Chief Medical Officer, Dr. Peter L. Nagy, and the Clinical Reporting Team led by Dr. Trey Langley present multiple case studies illustrating the value of high resolution CNV assessment, mitochondrial DNA analysis, uniparental disomy assessment, transcriptome/RNA sequencing, and repeat expansion screening from genetic sequencing datasets.
To listen to the webinar recording, please click here.
Patient Clinical Information: The proband is a 6 year-old female with a primary clinical phenotype of intellectual disability. Additionally, it was noted that the proband has proximal and distal weakness, muscle atrophy, and severe hypotonia. She has absent osteotendinous reflexes and severe hypoacusia (hearing loss). A thin corpus callosum was also noted on the patient’s brain MRI.
Family History: None reported.
Testing Ordered: MNG Exome™ Trio Sequencing + mtDNA
Genetic Findings: Through exome sequencing, the proband was found to have an apparent homozygous single nucleotide C duplication in the beta IV spectrin gene, SPTBN4. The proband’s father was shown to be heterozygous for the same C duplication, and the mother appears to be wild type, making this an interesting discovery.
When copy number data was analyzed, it was discovered that both the proband and the mother have a heterozygous deletion in the SPTBN4 gene that spans exons 6-11. The duplication variant previously noted is in exon 10. These findings explain why the proband appears to be homozygous for the duplication variant.
Based on the sequencing and copy number findings, this lead to a diagnosis of Congenital Myopathy with neuropathy and deafness, or CMND. This syndrome is a recently described autosomal recessive condition that is caused by mutations in the SPTBN4 gene. The beta IV spectrin protein is expressed in brain, peripheral nervous system, pancreas and skeletal muscle. CMND is characterized by severe hypotonia, muscle atrophy, areflexia and hearing loss. To date in the literature, only seven individuals that harbor either homozygous or compound heterozygous putative loss of function variants in the SPTBN4 gene have been reported. By combining whole exome sequencing and copy number analysis, MNG was able to help identify the genetic cause of the patient’s symptoms that otherwise would have gone undetected.
Figure 1: This image shows comparative sequencing reads from the proband and both parents. The red box highlights the C duplication found in SPTBN4 in both proband, apparently homozygous, and father, heterozygous. The green reference line seen in the mother’s sequencing reads shows no reads with a C duplication.
Figure 2: Copy number analysis visualization of proband, mother, and father. The green brackets show the area of interest between exons 6-11, and a heterozygous deletion of those exons in both the proband and mother. The arrow shows exon 10, where the previously noted duplication was detected through sequencing analysis.
Reported by: Heather Marton, PhD, Reporting, Laboratory Liaison