Six Novel ATM Gene Variants in Sri Lankan Patients with Ataxia Telangiectasia

Table 1

Comparison of mutation positions of the cases and its effect on protein sequence and phenotypic severity.

Case	Novel variants	Current evidence on the effect of the variant	Effect on ATM	Protein structure	AFP level (<10 μg/ml)	Phenotypic severity
1	c.7397C > A homozygous, missense	This variant is located in exon 48 of the ATM gene. Variants in this region overlaps 11 transcripts which code for mitochondrial fission factor interactor, a protein required for mitochondrial function.	p.Ala2466Glu	This single amino acid change did not affect the secondary and tertiary structures.	172.2	Mild ataxia; no family history of neurological, immunological disorders, or cancers
2	c.510_511delGT, homozygous, frameshift	This variant is located in exon 3 and has 14 overlapping transcripts. Frameshift variants lead to truncation of the ATM protein. This type of variants is associated with a more severe phenotype.	p.Tyr171fs	A partial protein was synthesized with only 2708 amino acids (wild type protein had 3056 amino acids)	200–300	Severe phenotype with multisystem involvement and recurrent infections; no family history of neurological, immunological disorders, or cancers
3	c.5347_5350delGAAA and c.8137A > T compound heterozygous	A deletion in the exon 33 of the ATM gene was observed. There are 8 overlapping transcripts in this region. The first variant leads to the formation of a truncated ATM protein and the second missense variant leads to a premature stop codon	p.Glu1783fs; p.Arg2713	The synthesized protein had only 1790 amino acids.	320.1	Severe early-onset ataxia, dysarthria, dystonia, and recurrent respiratory tract infections; no family history of neurological, immunological disorders, or cancers
4	c.1163A > C and c.5227A > C compound heterozygous	The first missense variant resides on exon 8; the second variant resides on exon 32 which is also a missense variant; missense variants were observed to result in a milder phenotype	p.Lys388Thr; p.Thr1743Pro	The secondary and the tertiary structures of the protein remained unchanged	49	Mild late-onset AT phenotype; no family history of neurological, immunological disorders, or cancers