Genetic Identification of a Common Collagen Disease in Puerto Ricans via Identity-by-Descent Mapping in a Health System

Abstract

48Achieving confidence in the causality of a disease locus is a complex task that often 49 requires supporting data from both statistical genetics and clinical genomics. Here we 50 describe a combined approach to identify and characterize a genetic disorder that 51 leverages distantly related patients in a health system and population-scale mapping. 52We utilize genomic data to uncover components of distant pedigrees, in the absence of 53 recorded pedigree information, in the multi-ethnic BioMe biobank in New York City. By 54 linking to medical records, we discover a locus associated with genetic relatedness that 55 also underlies extreme short stature. We link the gene, COL27A1, with a little-known 56 genetic disease, previously thought to be rare and recessive. We demonstrate that

Three new patients with Steel syndrome and a Puerto Rican specific COL27A1 mutation

“…We hypothesize that the Puerto Rican patients carry homozygous mutations due to identity by descent due to a founder mutation arising in Puerto Rico. This is supported byBelbin et al, 2017, who identified five patients of Puerto Rican ancestry with homozygous mutations and concordance of IBD haplotype with the mutations. This article was also able to determine a carrier rate of 1:51 for Puerto Ricans individuals.…”

“…When these surgeries have been performed, the affected joint tends to redislocate eventually.Eleven of the 14 patients with a molecular confirmation of Steel syndrome had the same homozygous c.2089G>C p.Gly697Arg mutation. Of these 11, 10 were Puerto Rican(Belbin et al, 2017;Gonzaga- Jauregui et al, 2015, our three patients) while one was from the United Arab Emirates(Gariballa et al, 2016). The patient from the United Arab Emirates had consanguineous parents (first cousins).…”

“…They reached a consensus that surgery to repair dislocations is not advisable because it leads to a poor outcome with recurrent hip dislocations (Flynn et al, 2010;Gonzaga-Jauregui et al, 2015;Steel et al, 1993). The causative gene, COL27A1, was not identified until 2015 by Gonzaga-Jauregui et al Only 11 patients have previously been published with COL27A1 mutations (Belbin et al, 2017;Gariballa et al, 2016;Gonzaga-Jauregui et al, 2015;Kotabagi, Shah, Shukla, & Girisha, 2016;Maddirevula et al, 2019;Thuresson et al, 2019). Eight of these patients had an apparent founder mutation, p.Gly697Arg in the Puerto Rican population (Belbin et al, 2017;Gariballa et al, 2016;Gonzaga-Jauregui et al, 2015).…”

“…The causative gene, COL27A1, was not identified until 2015 by Gonzaga-Jauregui et al Only 11 patients have previously been published with COL27A1 mutations (Belbin et al, 2017;Gariballa et al, 2016;Gonzaga-Jauregui et al, 2015;Kotabagi, Shah, Shukla, & Girisha, 2016;Maddirevula et al, 2019;Thuresson et al, 2019). Eight of these patients had an apparent founder mutation, p.Gly697Arg in the Puerto Rican population (Belbin et al, 2017;Gariballa et al, 2016;Gonzaga-Jauregui et al, 2015). Three patients were described with other mutations in COL27A1 and were not from Puerto Rico (Kotabagi et al, 2016;Maddirevula et al, 2019;Thuresson et al 2019).…”

“…Dr. Flynn was able to re-examine 18 of the 23 children originally seen in 1993. However, the Flynn et al (2010) paper does not distinguish which patients were previously evaluated, so it is unclear which patients did or did not receive follow up in 2010.Additionally, 11 more patients have been reported(Belbin et al, 2017;Gariballa et al, 2016;Gonzaga-Jauregui et al, 2015;Kotabagi et al, 2016;Maddirevula et al, 2019;Thuresson et al, 2019). In total, 48 patients have been previously published with the diagnosis of Steel Syndrome.…”