PMC3885782_01
Bilateral ocular telangiectasias. (A) Right eye. (B) Left eye.
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F1
Mild ocular telangiectasia was noted bilaterally, but there was no cutaneous telangiectasia (Fig. 1).
Sagittal T1-weighted magnetic resonance image of the patient's brain. Pronounced cerebellar atrophy is evident.
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F2
The serum alpha-fetoprotein (AFP) level was elevated (77.1 ng/mL), and brain magnetic resonance imaging (MRI) showed marked bilateral cerebellar atrophy (Fig. 2).
Giemsa-banded karyograms of the peripheral blood lymphocyte culture. (A) 46,XX,t(7;14)(q32;q11.2). (B) 46,XX,t(7;14)(p15.1;q11.2). (C) 46,XX,inv(7)(p1?q3?). Arrows indicate the breakpoints on each chromosome.
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F3
CD4 lymphocyte, 1.19x109/L; CD8 lymphocyte, 0.64x109/L; CD4/CD8 ratio, 1.85). Chromosome analysis, in which the patient's lymphocytes were stimulated with phytohemagglutinin and harvested for 72 hr, revealed balanced translocations or pericentric inversions involving 14q11.2, 7q32, and 7p15.1, besides metaphases with a regular female karyotype (Fig. 3): 46,XX,t(7;14) (q32;q11.2)[6]/46,XX,t(7;14)(p15.1;q11.2)[2]/46,XX,inv(7)(p1?q3?)[2]/46,XX[30].
Genomic DNA sequence analysis of the ATM gene in the patient and in her parents. (A) The solid arrow indicates a heterozygous A>C transition (c.3154-2A>C). (B) The open arrow indicates a heterozygous A>C transition (c.7090-2A>C).
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F4
ATM gene was performed and 2 novel intronic variants were identified: c.3154-2A>C in intron 21 and c.7090-2A>C in intron 48 on the basis of the reference sequence NM_000051.3 (Fig. 4). Additional genetic analysis of the patient's parents revealed that her father was heterozygous for the c.3154-2A>C variant, whereas her mother was heterozygous for the c.7090-2A>C variant.
Molecular effects of the c.3154-2A>C mutation. (A) The cDNA sequence from a normal control, and schematic representation of normal/aberrant mRNA splicing of the ATM gene. (B) The cDNA sequence from the patient. (C) The predicted amino acid sequence (inserted nucleotides are shaded).. Abbreviation: TA, thymine/adenine.
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F5
As expected, the c.3154-2A>C variant resulted in the insertion of 14 nucleotides from intron 21 into the transcript, causing a frameshift mutation that disrupted the 3' AG splice site (p.Ala1052Phefs*17; Fig. 5).
Molecular effects of the c.7090-2A>C mutation. (A) The cDNA sequence from a normal control, and schematic representation of normal/aberrant mRNA splicing of the ATM gene. (B) The cDNA sequence from the patient. (C) The predicted amino acid sequence (deleted nucleotides are shaded).. Abbreviation: TA, thymine/adenine.
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F6
The c.7090-2A>C variant resulted in the deletion of 4 nucleotides at exon 49, introducing a premature stop codon in exon 49 at amino acid position 2364 (p.Ala2364*; Fig. 6).