Can Ikaros mutation lead to intellectual disability?

Köse H., Kılıç Gültekin S. Ş.

ESID 1st PID Care in development School, Zagreb, Croatia, 15 - 17 October 2022, pp.1

  • Publication Type: Conference Paper / Full Text
  • City: Zagreb
  • Country: Croatia
  • Page Numbers: pp.1
  • Bursa Uludag University Affiliated: Yes



A 29-year-old male patient was referred to our hospital due to low serum Ig levels.  He was the fourth sibling of a non-consanguineous family. In his family, his mother and maternal grandmother had speech and hearing impairment associated with recurrent infections. The pedigree was shown in Figure1. The patient had osteomyelitis at the age of 18 months.  He suffered from recurrent pneumonia, soft tissue infections since his infancy. He was mentally retarded. The physical examination revealed the absence of tonsils. His head circumference was 54 cm (97 % percentile). Laboratory examination; showed severe panhypogammaglobulinemia and low B cell count. Antibody responses to diphtheria and tetanus vaccines were absent (Table1). A compound heterozygous missense mutation in IKZF1 gene c.500A>G/ p. His 167Arg was detected. 




In a cohort including six different families with a history of recurrent bacterial infections of the respiratory system, panhypogammaglobulinemia and autoimmune manifestations,   heterozygous IKZF1 mutations have been identified as an autosomal dominant type of inheritance(2). The patients have had defects in both innate and adaptive immune systems, in addition to progressive loss of B cells and functional anomalies of neutrophils, eosinophils, and myeloid dendritic cells, as well as T cells and monocytes. These mutations in IKZF1 reduce the DNA binding of IKAROS to its target sequence and give rise to an immunodeficiency syndrome primarily characterized by an antibody deficiency (2). Patients with IKZF-1 deficiency differ from CVID patients with other mutations by very low B cell counts, the presence of CD27+ memory B cells and plasma cells, and a family history consistent with autosomal dominant inheritance.Our patient had late-onset recurrent infections, panhypogammaglobulinemia, and severe B cell deficiency. His family history suggested autosomal dominant inheritance.


Ikaros family members also take place in central nervous system development. They are expressed in some striatal neurons.  Alsio et al showed that Ikaros is manifested mainly in early cortical progenitor cells and improves early-born neuronal development in the cerebral cortex (3). The gene coding cereblon (CRBN) which has an important role related to memory and learning processes was identified in patients with mild autosomal recessive intellectual disability (4,5). A study showed that CRBN binds to Ikaros by the N-terminal region and functions as a transcriptional modulator of Ikaros in the nucleus(5).

 Our patient had mental development delay since his infancy and no history of central nervous system infection. According to the EGY intelligence test result (IQ: 64), the patient was accepted as mild intellectual disability (MID). He had also obsessive-compulsive compulsions and prominent cognitive dysfunction. Recurrent infections and mental retardation were also present in her mother and grandmother. Although genetic testing of the mother and the grandmother could not be done, it was thought that they might have IKZ deficiency because of their intellectual limitations and frequent infections.

Despite the fact that the effect of the IKZF1 gene on brain development and cognitive functions on a cellular basis has been emphasized in the literature, no comment has been made on the mental status of patients with Ikaros defects. With this article, we wanted to draw attention to the impact of IKZF1 deficiency not only on immunodeficiency but also cognitive functions.