Linkage Disequilibrium Between SLC12A3 and HYDIN Pathogenic Variants in The Old Order Amish Community
Clinical Genetics and Therapeutics
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Primary Categories:
- Population Genetics
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Secondary Categories:
- Population Genetics
Introduction:
Gitelman syndrome (GS) is an autosomal recessive tubulopathy that affects the thiazide-sensitive sodium chloride cotransporter (NCCT). GS is characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The diagnosis is confirmed by biallelic pathogenic variants in the SLC12A3 gene. Clinical manifestations of GS can include salt cravings, fatigue, muscle weakness, dizziness, nocturia, and cardiac abnormalities. GS is typically diagnosed in adolescence or adulthood.
Primary Ciliary Dyskinesia (PCD) is an autosomal recessive ciliopathy that affects the C2b projection structure within the central pair apparatus, causing reduced/non-motile cilia. The diagnosis is confirmed by biallelic pathogenic variants in the HYDIN gene. Clinical manifestations of PCD can include respiratory distress in early infancy, chronic cough, recurrent bronchitis, pneumonia, otitis media, chronic rhinosinusitis, bronchiectasis, and infertility.
Concurrent pathogenic founder variants in SLC12A3 and HYDIN have been detected in several individuals of Old Order Amish ancestry who were evaluated at the Community Health Clinic (CHC), raising the possibility of linkage disequilibrium.
Nearly all individuals with Plain (Amish and Mennonite) ancestry descend from roughly 200 18th-century founders. Due to cultural practices, founder variants appear in higher frequencies, increasing the likelihood of sub-founder variants/haplotypes within the community.
In order to improve the care of individuals who are potentially affected by both disorders, we decided to further investigate the possibility of linkage disequilibrium between pathogenic founder variants in SLC12A3 and HYDIN in the Old Order Amish Community.
Methods:
Designed and performed by the Clinic for Special Children (CSC), the Plain Insight Panel (PIP) is a carrier screen for individuals of Plain ancestry. It includes 1,307 variants linked to autosomal recessive and dominant disorders prevalent in the Plain community, with an average of five variants detected per person.
Using preexisting data from all Plain Insight Panels (PIPs) performed by the CSC, including those sent from the CHC, the degree of linkage disequilibrium will be established.
Results:
The review of preexisting laboratory data revealed 102 SLC12A3 c.1-1471_893del heterozygotes and 40 of them also harbored the HYDIN variant (c.2047G>T, p. Glu683*, rs371610401, chr16_71067318_C_A). Of those 40 individuals with both variants, 10 came from the CHC while 22 came from the Central Pennsylvania Clinic (CPAC).
The joint variant calls in this data set clearly demonstrate linkage disequilibrium. The high frequency of the dual haplotype in the central PA Amish suggests the haplotype moved west from those settlements.
Conclusion:
Knowing there is linkage disequilibrium between the SLC12A3 and HYDIN pathogenic founder variants that could result in concurrent GD and PCD in individuals of Old Order Amish ancestry, guides clinicians to evaluate for both conditions simultaneously when either condition is suspected. This allows clinicians to optimize their assessments and resources to identify two conditions expeditiously and implement high quality care and disease management for the affected individual. This knowledge helps reduce the incidence of a missed diagnosis and has the potential to improve outcomes.
The observed lack of independent segregation between these alleles could be due to historical recombination events within the Amish population during westward migration in the U.S. Given the rarity of both conditions, we recommend testing for both variants in cases of clinical suspicion, especially within the Amish population. This study highlights the need for population-specific clinical guidelines to promote inclusive healthcare.
Gitelman syndrome (GS) is an autosomal recessive tubulopathy that affects the thiazide-sensitive sodium chloride cotransporter (NCCT). GS is characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The diagnosis is confirmed by biallelic pathogenic variants in the SLC12A3 gene. Clinical manifestations of GS can include salt cravings, fatigue, muscle weakness, dizziness, nocturia, and cardiac abnormalities. GS is typically diagnosed in adolescence or adulthood.
Primary Ciliary Dyskinesia (PCD) is an autosomal recessive ciliopathy that affects the C2b projection structure within the central pair apparatus, causing reduced/non-motile cilia. The diagnosis is confirmed by biallelic pathogenic variants in the HYDIN gene. Clinical manifestations of PCD can include respiratory distress in early infancy, chronic cough, recurrent bronchitis, pneumonia, otitis media, chronic rhinosinusitis, bronchiectasis, and infertility.
Concurrent pathogenic founder variants in SLC12A3 and HYDIN have been detected in several individuals of Old Order Amish ancestry who were evaluated at the Community Health Clinic (CHC), raising the possibility of linkage disequilibrium.
Nearly all individuals with Plain (Amish and Mennonite) ancestry descend from roughly 200 18th-century founders. Due to cultural practices, founder variants appear in higher frequencies, increasing the likelihood of sub-founder variants/haplotypes within the community.
In order to improve the care of individuals who are potentially affected by both disorders, we decided to further investigate the possibility of linkage disequilibrium between pathogenic founder variants in SLC12A3 and HYDIN in the Old Order Amish Community.
Methods:
Designed and performed by the Clinic for Special Children (CSC), the Plain Insight Panel (PIP) is a carrier screen for individuals of Plain ancestry. It includes 1,307 variants linked to autosomal recessive and dominant disorders prevalent in the Plain community, with an average of five variants detected per person.
Using preexisting data from all Plain Insight Panels (PIPs) performed by the CSC, including those sent from the CHC, the degree of linkage disequilibrium will be established.
Results:
The review of preexisting laboratory data revealed 102 SLC12A3 c.1-1471_893del heterozygotes and 40 of them also harbored the HYDIN variant (c.2047G>T, p. Glu683*, rs371610401, chr16_71067318_C_A). Of those 40 individuals with both variants, 10 came from the CHC while 22 came from the Central Pennsylvania Clinic (CPAC).
The joint variant calls in this data set clearly demonstrate linkage disequilibrium. The high frequency of the dual haplotype in the central PA Amish suggests the haplotype moved west from those settlements.
Conclusion:
Knowing there is linkage disequilibrium between the SLC12A3 and HYDIN pathogenic founder variants that could result in concurrent GD and PCD in individuals of Old Order Amish ancestry, guides clinicians to evaluate for both conditions simultaneously when either condition is suspected. This allows clinicians to optimize their assessments and resources to identify two conditions expeditiously and implement high quality care and disease management for the affected individual. This knowledge helps reduce the incidence of a missed diagnosis and has the potential to improve outcomes.
The observed lack of independent segregation between these alleles could be due to historical recombination events within the Amish population during westward migration in the U.S. Given the rarity of both conditions, we recommend testing for both variants in cases of clinical suspicion, especially within the Amish population. This study highlights the need for population-specific clinical guidelines to promote inclusive healthcare.