Recurrent TRAPPC11 variant in South Dakota’s Hutterite Population
Clinical Genetics and Therapeutics
-
Primary Categories:
- Clinical Genetics
-
Secondary Categories:
- Clinical Genetics
Introduction
The TRAPPC11 gene encodes a subunit of the transport protein particle (TRAPP) complex, which is a multisubunit protein complex important in intracellular trafficking. Variants in TRAPPC11 are associated with autosomal recessive limb-girdle muscular dystrophy 18 (LGMDR18), a rare disorder characterized by early onset myopathy, abnormal gait, and intellectual disability (MIM# 615356). Other common findings include, speech difficulties, seizures, and hypotonia. More rare findings include pathology of the eyes, heart, and liver.
Case Presentation
In this case series, we describe five patients with LGMDR18 caused by the same variant in TRAPPC11 from five different families of South Dakota Hutterite ancestry. All five patients came to medical attention for developmental delay. Common features also include ataxia, microcephaly, and hypotonia. The Hutterite population is a branch of the Anabaptist movement that was formed in the 1500s in Germany. Today, most of the Hutterite population live in colonies scattered throughout Canada and the midwestern and western United States. The highest concentration of Hutterite colonies in the United States can be found in South Dakota.
Diagnostic Workup
Trio whole exome sequencing in all five patients revealed homozygous TRAPPC11 c.1287+5G>A inherited from mother and father.
Discussion
Here we presented five cases of LGMDR18 caused by homozygous c.1287+5G>A variants in TRAPPC11. The fact that this same variant has appeared across multiple families with Hutterite ancestry as well as the relatively isolated nature of Hutterite colonies suggest that this could be a founder variant. This is supported by another report of the same TRAPPC11 c.1287+5G>A variant in five patients from two related Hutterite families, one in Canada and one in South Dakota. The Amish, Mennonite, and Hutterite Genetic Disorder database does not currently report LGMDR18 in the Hutterite population. Identifying this variant as a founder variant in the Hutterite population and adding it to the database could help guide clinicians when a patient with Hutterite ancestry presents with similar phenotypes. A recent review reported that there were 54 cases of LGMDR18 with 20 different pathogenic TRAPPC11 variants described in the literature. There is a wide spectrum of phenotypes associated with TRAPPC11 variants from adult-onset limb-girdle muscular dystrophy to infantile onset of systemic disease. The TRAPPC11 c.1287+5G>A variant accounts for 32 of the previously reported cases with 25 cases reported in the Roma population and five cases in two related Hutterite families. Consistent with our case series, in previous reports the TRAPPC11 c.1287+5G>A variant is associated with younger symptom onset and systemic involvement including microcephaly, seizures, and hypotonia. Few cases of LGMDR18 have been reported thus far, and adding five more cases to the reported literature can expand our knowledge LGMDR18 and increase awareness of the spectrum of LGMDR18 related phenotypes and specific phenotypes associated with the TRAPPC11 c.1287+5G>A variant.
The TRAPPC11 gene encodes a subunit of the transport protein particle (TRAPP) complex, which is a multisubunit protein complex important in intracellular trafficking. Variants in TRAPPC11 are associated with autosomal recessive limb-girdle muscular dystrophy 18 (LGMDR18), a rare disorder characterized by early onset myopathy, abnormal gait, and intellectual disability (MIM# 615356). Other common findings include, speech difficulties, seizures, and hypotonia. More rare findings include pathology of the eyes, heart, and liver.
Case Presentation
In this case series, we describe five patients with LGMDR18 caused by the same variant in TRAPPC11 from five different families of South Dakota Hutterite ancestry. All five patients came to medical attention for developmental delay. Common features also include ataxia, microcephaly, and hypotonia. The Hutterite population is a branch of the Anabaptist movement that was formed in the 1500s in Germany. Today, most of the Hutterite population live in colonies scattered throughout Canada and the midwestern and western United States. The highest concentration of Hutterite colonies in the United States can be found in South Dakota.
Diagnostic Workup
Trio whole exome sequencing in all five patients revealed homozygous TRAPPC11 c.1287+5G>A inherited from mother and father.
Discussion
Here we presented five cases of LGMDR18 caused by homozygous c.1287+5G>A variants in TRAPPC11. The fact that this same variant has appeared across multiple families with Hutterite ancestry as well as the relatively isolated nature of Hutterite colonies suggest that this could be a founder variant. This is supported by another report of the same TRAPPC11 c.1287+5G>A variant in five patients from two related Hutterite families, one in Canada and one in South Dakota. The Amish, Mennonite, and Hutterite Genetic Disorder database does not currently report LGMDR18 in the Hutterite population. Identifying this variant as a founder variant in the Hutterite population and adding it to the database could help guide clinicians when a patient with Hutterite ancestry presents with similar phenotypes. A recent review reported that there were 54 cases of LGMDR18 with 20 different pathogenic TRAPPC11 variants described in the literature. There is a wide spectrum of phenotypes associated with TRAPPC11 variants from adult-onset limb-girdle muscular dystrophy to infantile onset of systemic disease. The TRAPPC11 c.1287+5G>A variant accounts for 32 of the previously reported cases with 25 cases reported in the Roma population and five cases in two related Hutterite families. Consistent with our case series, in previous reports the TRAPPC11 c.1287+5G>A variant is associated with younger symptom onset and systemic involvement including microcephaly, seizures, and hypotonia. Few cases of LGMDR18 have been reported thus far, and adding five more cases to the reported literature can expand our knowledge LGMDR18 and increase awareness of the spectrum of LGMDR18 related phenotypes and specific phenotypes associated with the TRAPPC11 c.1287+5G>A variant.