Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly
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Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly. / Bilal, Muhammad; Khan, Hammal; Khan, Muhammad Javed; Haack, Tobias B.; Buchert, Rebecca; Liaqat, Khurram; Ullah, Kifayat; Ahmed, Sohail; Bharadwaj, Thashi; Acharya, Anushree; Peralta, Susana; Najumuddin; Ali, Hamid; Hasni, Muhammad Sharif; Schrauwen, Isabelle; Ullah, Asmat; Ahmad, Wasim; Leal, Suzanne M.
In: European Journal of Human Genetics, Vol. 31, No. 11, 2023, p. 1270-1274.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly
AU - Bilal, Muhammad
AU - Khan, Hammal
AU - Khan, Muhammad Javed
AU - Haack, Tobias B.
AU - Buchert, Rebecca
AU - Liaqat, Khurram
AU - Ullah, Kifayat
AU - Ahmed, Sohail
AU - Bharadwaj, Thashi
AU - Acharya, Anushree
AU - Peralta, Susana
AU - Najumuddin, null
AU - Ali, Hamid
AU - Hasni, Muhammad Sharif
AU - Schrauwen, Isabelle
AU - Ullah, Asmat
AU - Ahmad, Wasim
AU - Leal, Suzanne M.
N1 - Publisher Copyright: © 2023, The Author(s), under exclusive licence to European Society of Human Genetics.
PY - 2023
Y1 - 2023
N2 - Polydactyly is the most common limb malformation that occurs in 1.6–10.6 per one thousand live births, with incidence varying with ancestry. The underlying gene has been identified for many of the ~100 syndromes that include polydactyly. While for the more common form, nonsydromic polydactyly, eleven candidate genes have been reported. We investigated the underlying genetic cause of autosomal recessive nonsyndromic postaxial polydactyly in four consanguineous Pakistani families. Some family members with postaxial polydactyly also present with syndactyly, camptodactyly, or clinodactyly. Analysis of the exome sequence data revealed two novel homozygous frameshift deletions in EFCAB7: [c.830delG;p.(Gly277Valfs*5)]; in three families and [c.1350_1351delGA;p.(Asn451Phefs*2)] in one family. Sanger sequencing confirmed that these variants segregated with postaxial polydactyly, i.e., family members with postaxial polydactyly were found to be homozygous while unaffected members were heterozygous or wild type. EFCAB7 displays expressions in the skeletal muscle and on the cellular level in cilia. IQCE-EFCAB7 and EVC-EVC2 are part of the heterotetramer EvC complex, which is a positive regulator of the Hedgehog (Hh) pathway, that plays a key role in limb formation. Depletion of either EFCAB7 or IQCE inhibits induction of Gli1, a direct Hh target gene. Variants in IQCE and GLI1 have been shown to cause nonsyndromic postaxial polydactyly, while variants in EVC and EVC2 underlie Ellis van Creveld and Weyers syndromes, which include postaxial polydactyly as a phenotype. This is the first report of the involvement of EFCAB7 in human disease etiology.
AB - Polydactyly is the most common limb malformation that occurs in 1.6–10.6 per one thousand live births, with incidence varying with ancestry. The underlying gene has been identified for many of the ~100 syndromes that include polydactyly. While for the more common form, nonsydromic polydactyly, eleven candidate genes have been reported. We investigated the underlying genetic cause of autosomal recessive nonsyndromic postaxial polydactyly in four consanguineous Pakistani families. Some family members with postaxial polydactyly also present with syndactyly, camptodactyly, or clinodactyly. Analysis of the exome sequence data revealed two novel homozygous frameshift deletions in EFCAB7: [c.830delG;p.(Gly277Valfs*5)]; in three families and [c.1350_1351delGA;p.(Asn451Phefs*2)] in one family. Sanger sequencing confirmed that these variants segregated with postaxial polydactyly, i.e., family members with postaxial polydactyly were found to be homozygous while unaffected members were heterozygous or wild type. EFCAB7 displays expressions in the skeletal muscle and on the cellular level in cilia. IQCE-EFCAB7 and EVC-EVC2 are part of the heterotetramer EvC complex, which is a positive regulator of the Hedgehog (Hh) pathway, that plays a key role in limb formation. Depletion of either EFCAB7 or IQCE inhibits induction of Gli1, a direct Hh target gene. Variants in IQCE and GLI1 have been shown to cause nonsyndromic postaxial polydactyly, while variants in EVC and EVC2 underlie Ellis van Creveld and Weyers syndromes, which include postaxial polydactyly as a phenotype. This is the first report of the involvement of EFCAB7 in human disease etiology.
U2 - 10.1038/s41431-023-01450-5
DO - 10.1038/s41431-023-01450-5
M3 - Journal article
C2 - 37684519
AN - SCOPUS:85170036476
VL - 31
SP - 1270
EP - 1274
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 11
ER -
ID: 367710809