Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B
Por:
Palencia-Campos A, Martínez-Fernández ML, Altunoglu U, Soto-Bielicka P, Torres A, Marín P, Aller E, Sentürk L, Berköz Ö, Yildiran M, Kayserili H, Gil-Camarero E, Colli-Lista G, Sanchís-Calvo A, Carretero A, ECEMC Working Group on Polydactyly, Guillén-Navarro E, López-González V, Ballesta-Martínez M, Rosell J, Aglan MS, Temtamy S, Otaify GA, Cuevas-Catalina L, Torres-Saavedra MN, Nevado J, Tenorio J, Lapunzina P, Bermejo-Sánchez E and Ruiz-Pérez VL
Publicada:
1 ene 2020
Ahead of Print:
1 nov 2019
Resumen:
Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAP-B corresponding to a more rudimentary extra-digit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP-A, may include syndromic features. Moreover, two heterozygous subjects carrying only one inactive copy of GLI1 were also identified with PAP. Herein, we aimed to determine the level of involvement of GLI1 in isolated PAP, a condition previously established to be autosomal dominantly inherited with incomplete penetrance. We analyzed the coding region of GLI1 in 95 independent probands with nonsyndromic PAP and found 11.57% of these subjects with single heterozygous pathogenic variants in this gene. The detected variants lead to premature termination codons or result in amino acid changes in the DNA-binding domain of GLI1 that diminish its transactivation activity. Family segregation analysis of these variants was consistent with dominant inheritance with incomplete penetrance. We conclude that heterozygous changes in GLI1 underlie a significant proportion of sporadic or familial cases of isolated PAP-A/B.
Filiaciones:
Palencia-Campos A:
Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, 28029, Madrid, Spain
CIBER de Enfermedades Raras (CIBERER), Institute of Health Carlos III, Spain
Martínez-Fernández ML:
ECEMC (Spanish Collaborative Study of Congenital Malformations), Research Center on Congenital Anomalies (CIAC), Institute of Health Carlos III, 28029, Madrid, Spain
Altunoglu U:
Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
Soto-Bielicka P:
Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, 28029, Madrid, Spain
Torres A:
Paediatric Unit, Hospital San Juan de La Cruz. Úbeda (Jaén), Spain
Marín P:
Dysmorphology and Neonatology Service. Hospital Universitario y Politécnico La Fe., Valencia, Spain
Aller E:
CIBER de Enfermedades Raras (CIBERER), Institute of Health Carlos III, Spain
Genetic Unit, Hospital La Fe, Valencia, Spain
Sentürk L:
Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
Berköz Ö:
Department of Reconstructive and aesthetic Surgery, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
Yildiran M:
Department of Reconstructive and aesthetic Surgery, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
Kayserili H:
Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey
Gil-Camarero E:
Paediatric Unit, Hospital Comarcal, Laredo, (Cantabria), Spain
Colli-Lista G:
Paediatric Unit, Hospiten Estepona, Estepona, (Málaga), Spain
:
Paediatric Unit, Hospital Universitario Doctor Peset, Valencia, Spain
Carretero A:
Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, 28029, Madrid, Spain
ECEMC Working Group on Polydactyly:
Paediatric Units from different hospitals†, all part of ECEMC (Spanish Collaborative Study of Congenital Malformations) Clinical Network, Spain
Guillén-Navarro E:
CIBER de Enfermedades Raras (CIBERER), Institute of Health Carlos III, Spain
Genetic Medicine Unit, Paediatric Unit, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, El Palmar, Murcia, Spain
López-González V:
CIBER de Enfermedades Raras (CIBERER), Institute of Health Carlos III, Spain
Genetic Medicine Unit, Paediatric Unit, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, El Palmar, Murcia, Spain
Ballesta-Martínez M:
CIBER de Enfermedades Raras (CIBERER), Institute of Health Carlos III, Spain
Genetic Medicine Unit, Paediatric Unit, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, El Palmar, Murcia, Spain
Rosell J:
CIBER de Enfermedades Raras (CIBERER), Institute of Health Carlos III, Spain
Genetic Unit, Hospital Son Espases, Palma de Mallorca, Balearic, Islands, Spain
Aglan MS:
Department of Clinical Genetics. Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
Temtamy S:
Department of Clinical Genetics. Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
Otaify GA:
Department of Clinical Genetics. Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
Cuevas-Catalina L:
ECEMC (Spanish Collaborative Study of Congenital Malformations), Research Center on Congenital Anomalies (CIAC), Institute of Health Carlos III, 28029, Madrid, Spain
Torres-Saavedra MN:
ECEMC (Spanish Collaborative Study of Congenital Malformations), Research Center on Congenital Anomalies (CIAC), Institute of Health Carlos III, 28029, Madrid, Spain
CS Federica Montseny, Unidad Asistencial Sureste, Madrid, Spain
Nevado J:
Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046, Madrid, Spain
Tenorio J:
CIBER de Enfermedades Raras (CIBERER), Institute of Health Carlos III, Spain
Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046, Madrid, Spain
Lapunzina P:
CIBER de Enfermedades Raras (CIBERER), Institute of Health Carlos III, Spain
Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046, Madrid, Spain
Bermejo-Sánchez E:
ECEMC (Spanish Collaborative Study of Congenital Malformations), Research Center on Congenital Anomalies (CIAC), Institute of Health Carlos III, 28029, Madrid, Spain
Institute of Rare Diseases Research (IIER), Institute of Health Carlos III, 28029, Madrid, Spain
Ruiz-Pérez VL:
Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, 28029, Madrid, Spain
CIBER de Enfermedades Raras (CIBERER), Institute of Health Carlos III, Spain
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