Autosomal recessive intellectual developmental disorder-3 (MRT3) is caused by homozygous or compound heterozygous mutations in the CC2D1A gene. Intellectual disability (ID) and ASD are the most common developmental disorders and are often accompanied by comorbidity in humans.
In addition to neurological abnormalities, the CC2D1A gene is associated with human heterotaxis, ciliary dysfunction, microphthalmia, aniridia, corneal opacity and renal agenesis.
The first deletion described concerns 3,589 nucleotides starting in intron 13 and ending in intron 16 of the CC2D1A gene. It was identified in Israeli-Arab families homozygous for the deletion with intellectual developmental disorder-3 in 2006 (MRT3, OMIM:608443). The deletion introduces a frameshift, creating a nonsense and a stop codon at position 438. Peptides of 30-amino acid are produced from mutated gene.
Second, a frameshift mutation (c.811delG; p.A271Pfs*30) was identified in a multiplex family (Turkey). All (3 females) of the affected females were homozygous for this mutation with normal height and head circumference. Other clinical signs included ASD, developmental delays including speech delays and seizures.
Loss-of function mutations in CC2D1A cause a spectrum of non-syndromic neurodevelopmental deficits and ASD. Some CC2D1A variants are classified as references of uncertain significance, pathogenic or probably pathogenic.
In 2006, mutations in the CC2D1A gene were considered responsible for NSID and ASD. A homozygous deletion of 3,589 nucleotides was identified in the CC2D1A gene (IVS13-16DEL). This mutation was observed in 7 males and 8 females in the 9 different consanguine families. All patients were homozygous and all parents were heterozygous. This finding is consistent with autosomal recessive inheritance.
The initial clinical presentation in all affected family members was delayed psychomotor development in early childhood and severe mental retardation. None had autistic and dysmorphic features or seizures. The parents were heterozygous for the mutation.
In 2018, another homozygous mutation (c.811delG; p.A271Pfs*30) was reported in the cases of three sisters suffering from ID, ASD, developmental delay and seizure in a multiplex consanguineous family.
The parents were heterozygous for the mutation. All affected women had normal height and head circumference. Other clinical sings were IS, ASD, developmental delay including speech delay and seizures.
In 2022, a de novo missense mutation (p.V499M) was reported in a 6 year old boy from Turkey with the clinical findings of ASD and speech delay. The same mutation was reported again with another study the same year. The main clinical signs were microphthalmia, aniridia, corneal opacity and renal agenesis.
Several heterozygous pathogenic variants have been identified in patients with ASD. The relationship between CC2D1A and ASD has also been validated with the animal models and functional studies.