Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide

Abstract

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy

“…Taken together with population data, these AOH data from ES suggest that TNNT3 : c.481-1G>A may represent a Clan Genomics derived founder mutation in the Latino population. 10 , 11 The nucleotide is well conserved ( figure 2B ), and the variant is predicted damaging by multiple variant annotation tools (MutationTaster: Disease causing; CADD score: 33) and splicing predictors ( table 1 ).…”

Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant

“…Of note, both frameshift mutations, c.1684delC and c.1794delC, occur in runs of 5C and 3C nucleotides, respectively. These mutations likely occurred de novo in a distant member of the clan by slippage during DNA replication and were homozygozed by identity‐by‐descent in the family given consanguinity (Bi et al, 2006; Gonzaga‐Jauregui et al, 2020; Lupski et al, 2011). All three mutant mRNAs, the two reported by Monies et al and the one reported herein, likely escape NMD and thus make a protein mutated at the carboxy‐terminus that may cause LoF by acting as either a null or hypomorphic allele.…”

“…shinyapps.io/nmdescpredictor/)(Coban-Akdemir et al, 2018). To quantitate degree of consanguinity and delineate potential identity-by-decent (IBD) intervals, unphased ES data were analyzed using BafCalculator (https://github.com/BCM-Lupskilab/BafCalculator) according to the BafCalculator algorithm described previously(Gambin et al, 2017;Gonzaga-Jauregui et al, 2020). The variant was located within 10.6 and 10.8 Mb intervals of absence of heterozygosity (AOH) blocks with a total genome-wide AOH size of 401.74 and 287.24 Mb in the proband (BAB13277) and affected sister (BAB13280), respectively (Figure1(d)).4 | DISCUSSIONWe report a family from Egypt with a novel homozygous frame-shift variant c.1684delC p.(Arg562Alafs*56) in the last coding exon of ALKBH8.…”

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits

“…Disease causing variants with such high allele frequencies tend to be found in established recessive disorders, often attributed to founder mutation alleles. 4 In contrast, if a yet-to-be- defined recessive disease trait gene does not have pathogenic alleles represented at a sufficient population frequency, disease discovery and annotation of the gene would be greatly hampered due to the extremely low incidence and difficulty in ascertaining affected individuals, even when considering a world-wide population of 7.8 billion. An exception to this rule occurs when disease gene discovery research is conducted in populations with an elevated coefficient of consanguinity and autozygosity.…”

“…In this circumstance, the allele pool shrinks to the Clan of the patient’s extended family, which dramatically escalates the effective disease-allele frequency. 4 ; 5 Thus, the probability of ascertaining patients with the recessive disorder increases exponentially, even when all existing alleles are ultra-rare in sampling the general population. 6…”