Identification of small and large genomic candidate variants in bovine pulmonary hypoplasia and anasarca syndrome
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Identification of small and large genomic candidate variants in bovine pulmonary hypoplasia and anasarca syndrome. / Häfliger, I. M.; Wiedemar, N.; Švara, T.; Starič, J.; Cociancich, V.; Šest, K.; Gombač, M.; Paller, T.; Agerholm, J. S.; Drögemüller, C.
I: Animal Genetics, Bind 51, Nr. 3, 2020, s. 382-390.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Identification of small and large genomic candidate variants in bovine pulmonary hypoplasia and anasarca syndrome
AU - Häfliger, I. M.
AU - Wiedemar, N.
AU - Švara, T.
AU - Starič, J.
AU - Cociancich, V.
AU - Šest, K.
AU - Gombač, M.
AU - Paller, T.
AU - Agerholm, J. S.
AU - Drögemüller, C.
PY - 2020
Y1 - 2020
N2 - The pulmonary hypoplasia and anasarca syndrome (PHA) is a congenital lethal disorder, which until now has been reported in cattle and sheep. PHA is characterized by extensive subcutaneous fetal edema combined with hypoplasia or aplasia of the lungs and dysplasia of the lymphatic system. PHA is assumed to be of genetic etiology. This study presents the occurrence of PHA in two different cattle breeds and their genetic causation. Two PHA cases from one sire were observed in Slovenian Cika cattle. Under the assumption of monogenic inheritance, genome-wide homozygosity mapping scaled down the critical regions to 3% of the bovine genome including a 43.6 Mb-sized segment on chromosome 6. Whole-genome sequencing of one case, variant filtering against controls and genotyping of a larger cohort of Cika cattle led to the detection of a likely pathogenic protein-changing variant perfectly associated with the disease: a missense variant on chromosome 6 in ADAMTS3 (NM_001192797.1: c.1222C>T), which affects an evolutionary conserved residue (NP_001179726.1: p.(His408Tyr)). A single PHA case was found in Danish Holstein cattle and was whole-genome sequenced along with its parents. However, as there was no plausible private protein-changing variant, mining for structural variation revealed a likely pathogenic trisomy of the entire chromosome 20. The identified ADAMTS3 associated missense variant and the trisomy 20 are two different genetic causes, which shows a compelling genetic heterogeneity for bovine PHA.
AB - The pulmonary hypoplasia and anasarca syndrome (PHA) is a congenital lethal disorder, which until now has been reported in cattle and sheep. PHA is characterized by extensive subcutaneous fetal edema combined with hypoplasia or aplasia of the lungs and dysplasia of the lymphatic system. PHA is assumed to be of genetic etiology. This study presents the occurrence of PHA in two different cattle breeds and their genetic causation. Two PHA cases from one sire were observed in Slovenian Cika cattle. Under the assumption of monogenic inheritance, genome-wide homozygosity mapping scaled down the critical regions to 3% of the bovine genome including a 43.6 Mb-sized segment on chromosome 6. Whole-genome sequencing of one case, variant filtering against controls and genotyping of a larger cohort of Cika cattle led to the detection of a likely pathogenic protein-changing variant perfectly associated with the disease: a missense variant on chromosome 6 in ADAMTS3 (NM_001192797.1: c.1222C>T), which affects an evolutionary conserved residue (NP_001179726.1: p.(His408Tyr)). A single PHA case was found in Danish Holstein cattle and was whole-genome sequenced along with its parents. However, as there was no plausible private protein-changing variant, mining for structural variation revealed a likely pathogenic trisomy of the entire chromosome 20. The identified ADAMTS3 associated missense variant and the trisomy 20 are two different genetic causes, which shows a compelling genetic heterogeneity for bovine PHA.
KW - cattle
KW - chromosomal aberration
KW - genetic disorder
KW - Mendelian
KW - monogenic
KW - precision medicine
KW - rare disease
KW - trisomy
U2 - 10.1111/age.12923
DO - 10.1111/age.12923
M3 - Journal article
C2 - 32069517
AN - SCOPUS:85079704384
VL - 51
SP - 382
EP - 390
JO - Animal Genetics
JF - Animal Genetics
SN - 0268-9146
IS - 3
ER -
ID: 237100066