2q14.3 deletion disrupting CNTNAP5 in a girl with intellectual impairment, thin corpus callosum, and microcephaly.
The contactin-associated proteins (CNTNAP) are a subgroup of the neurexin family, predominantly expressed in the central nervous system (CNS). These genes are essential in neurodevelopment and appropriate CNS functioning; contributing to neuron excitation, signaling, conduction, and myelination. Of the five genes, little is known about CNTNAP5. In contrast, the other CNTNAP genes are well defined, and have been linked to a range of neurodevelopmental conditions, such as childhood epilepsy, autoimmune encephalitis, autism spectrum disorder, and learning and motor delay. The role of mutations in CNTNAP5 remains to be well-established.
The authors report a patient who had 838 kb deletion at 2q14.3 that involved only CNTNAP5. The most prominent characteristics of the patient were microcephaly, thin corpus callosum, and cognitive impairment. At age 9 all cognitive tests were below the 5th centile. The most striking test result was her processing speed, at 0.4th centile. These results indicate a degree of intellectual impairment and developmental delay, particularly in processing speed. The physical examination revealed also mild micrognathia, full cheeks, and prominent incisors. Based on the patient’s loss of function only in CNTNAP5, the deletion acts as a strong candidate for the cause of the patient’s phenotype.
There are several previously reported cases with deletions involving CNTNAP5, but in all these cases other genes in this area were also deleted. Based on this report, the CNTNAP5 deletion likely contributes to developmental delays and neurological impairment. In rare variants, it increases autism spectrum disorder susceptibility and risk of major depressive disorder. Due to the complexity of the multi-gene mutations, it proves difficult to confidently identify the contribution of CNTNAP5, though the data support the asserted function.
The patient of focus had a small deletion that only affected CNTNAP5. To date, there are no other cases of a deletion limited to this single gene, providing a rare opportunity to identify its true function. The novel deletion provides strong support of its suspected contribution in appropriate neurodevelopment and functioning.
Ludington EG, Yu S, Bae HA, Barnett CP. Novel de novo 2q14.3 deletion disrupting CNTNAP5 in a girl with intellectual impairment, thin corpus callosum, and microcephaly. Am J Med Genet Part A. 2020, online ahead of print.