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Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family
Author(s) -
Khan Muhammad Ismail,
Latif Muhammad,
Saif Maria,
Ahmad Hilal,
Khan Atta Ullah,
Naseer Muhammad Imran,
Hussain Hafiz Muhammad Jafar,
Jelani Musharraf
Publication year - 2021
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.3279
Subject(s) - joubert syndrome , exome sequencing , missense mutation , sanger sequencing , genetics , biology , hypotonia , ciliopathies , genetic counseling , compound heterozygosity , phenotype , intellectual disability , penetrance , gene , mutation
Abstract Background Joubert syndrome (JBTS) is a heterogenous disorder characterized by intellectual disability, developmental delays, molar tooth sign in brain imaging, hypotonia, ocular motor apraxia and overlapping features of ciliopathies. There are 36 clinical subtypes of JBTS, with an equal number of genes known so far for this phenotype. Methods Whole exome sequencing (WES) and Sanger sequencing were performed for the molecular diagnosis of a Pakhtun family affected with Joubert syndrome type 9 (JBTS9). Results A novel homozygous missense variant (c.4417C>G; Pro1473Ala) in exon 34 was identified in coiled‐coil and C2 domains‐containing the protein 2A ( CC2D2A ; NM_001080522) gene. The variant co‐segregated in autosomal recessive fashion within the family and was not found in 200 ethnically matched unaffected individuals. In silico analyses supported the pathogenic effect of the altered CC2D2A protein. Conclusions To the best of our knowledge, this is the first report of CC2D2A alteration co‐segragating with a JBTS9 phenotype in a Pakhtun family from Pakistan. Our findings broaden the pathogenic spectrum of JBTS9, adding a novel variant to CC2D2A variation pool. WES analysis is a successful molecular diagnostic tool for rare genetic disorders, especially in those populations where the marriage of cousins is more frequent. Efficient and accurate genetic testing and counselling of the affected families are helpful for patient management and for reducing the disease burden in future generations.