A medical odyssey of a 72-year-old man with Charcot-Marie-Tooth disease type 2 newly diagnosed with biallelic variants in SORD gene causing sorbitol dehydrogenase deficiency.

A 72-year-old man was referred to the Undiagnosed Diseases Network (UDN) because of gradual progressive weakness in both lower extremities for the past 45 years. He was initially diagnosed as having Charcot-Marie-Tooth disease type 2 (CMT2) without a defined molecular genetic cause. Exome sequencing (ES) failed to detect deleterious neuromuscular variants. Very recently, biallelic variants in sorbitol dehydrogenase (SORD) were discovered to be a novel cause of inherited neuropathies including CMT2 or distal hereditary motor neuropathy (dHMN) referred to as Sorbitol Dehydrogenase Deficiency with Peripheral Neuropathy (SORDD, OMIM 618912). The most common variant identified was c.757delG; p.A253Qfs*27. Through the Vanderbilt UDN clinical site, this patient was formally diagnosed with SORDD after the identification of homozygosity for the above SORD frameshift through UDN Genome Sequencing (GS). His medical odyssey was solved by GS and detection of extremely high levels of sorbitol. The diagnosis provided him the opportunity to receive potential treatment with an investigational drug in a clinical trial for SORDD. We suggest that similar studies be considered in other individuals thought to possibly have CMT2 or dHMN.

Lessons learned: next-generation sequencing applied to undiagnosed genetic diseases.

Rare genetic disorders, when considered together, are relatively common. Despite advancements in genetics and genomics technologies as well as increased understanding of genomic function and dysfunction, many genetic diseases continue to be difficult to diagnose. The goal of this Review is to increase the familiarity of genetic testing strategies for non-genetics providers. As genetic testing is increasingly used in primary care, many subspecialty clinics, and various inpatient settings, it is important that non-genetics providers have a fundamental understanding of the strengths and weaknesses of various genetic testing strategies as well as develop an ability to interpret genetic testing results. We provide background on commonly used genetic testing approaches, give examples of phenotypes in which the various genetic testing approaches are used, describe types of genetic and genomic variations, cover challenges in variant identification, provide examples in which next-generation sequencing (NGS) failed to uncover the variant responsible for a disease, and discuss opportunities for continued improvement in the application of NGS clinically. As genetic testing becomes increasingly a part of all areas of medicine, familiarity with genetic testing approaches and result interpretation is vital to decrease the burden of undiagnosed disease.