Hereditary Sensory and Autonomic Neuropathy 2B Caused by a Novel RETREG1 Mutation (c.765dupT) and Paternal Uniparental Isodisomy of Chromosome 5

Hereditary sensory and autonomic neuropathy (HSAN) 2B is a rare disease and has been reported mostly in offspring of consanguineous parents. Here we report the case of a patient born to non-consanguineous parents who was diagnosed with HSAN 2B caused due to a novel frameshift mutation (NM_001034850.2: c.765dupT/p.Gly256TrpfsTer7) in the RETREG1 gene and paternal uniparental isodisomy of chromosome 5. Uniparental isodisomy of chromosome 5 is also a rare condition, and these two rare events lead to homozygous expression of a recessive mutation, as in the present case. Clinicians should be aware that autosomal recessive disorders due to homozygous variants can occur because of uniparental disomy in offspring of non-consanguineous parents.

Hereditary sensory and autonomic neuropathy (HSAN) 2B is a rare disease and has been reported mostly in offspring of consanguineous parents. Here we report the case of a patient born to non-consanguineous parents who was diagnosed with HSAN 2B caused due to a novel frameshift mutation (NM_001034850.2: c.765dupT/p.Gly256TrpfsTer7) in the RETREG1 gene and paternal uniparental isodisomy of chromosome 5. Uniparental isodisomy of chromosome 5 is also a rare condition, and these two rare events lead to homozygous expression of a recessive mutation, as in the present case. Clinicians should be aware that autosomal recessive disorders due to homozygous variants can occur because of uniparental disomy in offspring of non-consanguineous parents.
Keywords: hereditary sensory and autonomic neuropathy, consanguineous marriage, frameshift mutation, uniparental isodisomy, homozygous BACKGROUND To date, a total of eight families related to hereditary sensory and autonomic neuropathy (HSAN) 2B due to RETREG1 mutation have been reported since Kurth et al. (2009) first reported four such families Murphy et al., 2012;Ilgaz Aydinlar et al., 2014;Wakil et al., 2018). HSAN 2B is characterized by progressive sensory deficit and variable autonomic and motor involvement. Because few RETREG1 mutations have been reported, there is no clear description of the phenotype of HSAN 2B.
Since the first report of uniparental disomy of chromosome 5 in 1994, several cases have been additionally reported (Brzustowicz et al., 1994;Seal et al., 2006;Lin et al., 2007;Garcia et al., 2014;Melone et al., 2014;Numata et al., 2014;Janecke et al., 2015;Wang et al., 2015). Uniparental disomy of chromosome 5 is also a rare condition with no clear description of clinical significance such as imprinting effects. Here, we describe a novel frameshift mutation (NM_001034850.2: c.765dupT/p. Gly256TrpfsTer7) in the RETREG1 gene and paternal uniparental isodisomy of chromosome 5 in a patient diagnosed with HSAN 2B. Written informed consent was obtained from the patient for the publication of this case report after she had been briefed about the study.

CASe PReSeNTATION
The proband was a 22-year-old female who visited our clinic for evaluation of a sensory disturbance in both lower extremities and unstable gait. The patient was born to non-consanguineous parents in a Korean family with no familial history of hereditary disorders. She had normal birth history and developmental milestones. Her symptoms had started to appear at the age of approximately 10 years and gradually progressed. The patient exhibited a decreased sensitivity to pain, temperature, touch, and vibration and decreased sense of position in both lower extremities, with an ulcer on her left toe, which had lasted more than a year and had healed recently ( Figure 1A). She had mild distal motor weakness in her lower extremities (Medical Research Council scale 4), spasticity, and increased deep tendon reflex in both lower extremities. She exhibited normal intelligence and no autonomic symptoms. A nerve conduction study indicated sensory axonal polyneuropathy more than motor, and sympathetic skin response was impaired on both the soles. The patient underwent genetic testing, using a targeted gene sequencing panel, analyzing 410 genes associated with genetic neuromuscular diseases. Genomic DNA was extracted from the peripheral blood of the patient. Library preparation and target enrichment were performed using the hybridization capture method. Custom oligo design and synthesis were done by Agilent (USA). Massively parallel sequencing was performed using 2 × 150 bp in the paired end mode of NextSeq platform (Illumina, San Diego, CA). A novel frameshift homozygous variation was detected in the patient's RETREG1 gene, c.765dupT/p.Gly256TrpfsTer7. However, of the patient's parents, only the father was identified as a carrier of the variation in Sanger sequencing ( Figure 1B). Furthermore, a single nucleotide polymorphism array (Infinium Global Screening Array-24+ v2.0, Illumina) was performed with DNA   from the patient and her parents, revealing paternal uniparental isodisomy of chromosome 5 (Figures 1C, D).

DISCUSSION
Clinical features of the present case and all previously reported cases of HSAN 2B have been summarized in Table 1. HSAN 2B is a rare genetic disorder and has been mostly reported in consanguineous families, unlike our case. There have been six pathologic variants in the RETREG including the present case, which was the frameshift, nonsense, and splice site type. Furthermore, all reported patients were the homozygous genotype which suspicious of consanguineous family. All cases have similar characteristics including early onset (1st-2nd decade), progressive sensory disturbance, distal motor weakness, skin ulcer, and/or spasticity, with variable autonomic involvement. Although the pathomechanism through which RETREG mutation causes HSAN 2B was postulated to be the inhibition of turnover and degradation of the endoplasmic reticulum, it is largely unknown (Islam et al., 2018). In addition, uniparental disomy of chromosome 5 has been rarely reported, with approximately 15 cases reported to date (http://upd-tl.com/upd.html); some of these cases have been considered to exhibit homozygous expression of a recessive mutation ( Table 2) (Brzustowicz et al., 1994;Seal et al., 2006;Lin et al., 2007;Garcia et al., 2014;Melone et al., 2014;Numata et al., 2014;Janecke et al., 2015;Wang et al., 2015). Imprinting effects due to uniparental disomy of chromosome 5 are possible, but this has not been established. Further studies on uniparental disomy of chromosome 5 are necessary to clarify the prevalence and possibility of imprinting defects.
We reported the case of a patient born to non-consanguineous parents who was diagnosed with HSAN 2B caused due to a novel frameshift mutation (c.765dupT/p.Gly256TrpfsTer7) in the RETREG1 gene and paternal uniparental isodisomy of chromosome 5. Clinicians should be aware that autosomal recessive disorders due to homozygous variants can occur because of uniparental disomy in offspring of non-consanguineous parents.

DATA AVAILABILITY STATeMeNT
The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

eTHICS STATeMeNT
This study was carried out in accordance with the recommendations of the institutional research review board of the Catholic University of Korea, Incheon St. Mary's Hospital with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the institutional research review board of the Catholic University of Korea, Incheon St. Mary's Hospital.