Exome sequencing revealed a novel splice site variant in the ALX1 gene underlying frontonasal dysplasia.
Frontonasal dysplasia (FND) is a heterogeneous group of disorders characterized by hypertelorism, telecanthus, broad nasal root, wide prominent nasal bridge, short and wide nasal ridge, broad columella and smooth philtrum. To date one X-linked and three autosomal recessive forms of FND have been reported in different ethnic groups. We sought to identify the gene responsible for FND in a consanguineous Pakistani family segregating the disorder in autosomal recessive pattern. Genome-wide homozygosity mapping using 250KNsp array revealed five homozygous regions in the selected affected individuals. Exome sequencing found a novel splice acceptor site variant (c.661-1G>C: NM_006982.2) in ALX1. Sanger sequencing confirmed the correct segregation of the pathogenic variant in the whole family. Our study concludes that the splice site variant identified in the ALX1 gene causes mild form of FND.
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Ullah
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Kalsoom
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Umair
Department of Healthcare Biotechnology, Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Science & Technology (NUST), Islamabad, Pakistan.
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John
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Ansar
Center for Genetics and Inherited Diseases, Taibah University, Al Madinah Al Munawarah, Saudi Arabia.
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Basit
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Ahmad
D044466:Asian People; D003241:Consanguinity; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005145:Face / Q000002:abnormalities* / Q000473:pathology; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics
C489985:ALX1 protein, human; D018398:Homeodomain Proteins; D022821:RNA Splice Sites
ALX1; acceptor-splice-site mutation; broad nasal root; frontonasal Dysplasia; homozygosity mapping and exome sequencing; hypertelorism; wide prominent nasal bridge