Compound heterozygous variants including a novel copy number variation in a child with atypical ataxia-telangiectasia: a case report

Abstract

Background Ataxia-telangiectasia is a rare autosomal recessive, neurodegenerative disorder caused by alterations in the ATM gene. The majority of ATM pathogenic variants are frameshift or nonsense variants which are predicted to truncate the whole ATM protein. Herein, we report on an ataxia telangiectasia child with atypical phenotype who was identified as compound heterozygous for two ATM variants involving a previously described pathogenic single nucleotide variation (SNV) and a novel copy number variation (CNV). Case presentation A 6-year-old boy presented with delayed development and oculomotor apraxia. Brain magnetic resonance imaging showed interval development of mild atrophy in the cerebellum. Serum alpha fetoprotein level was in normal range. Next-generation sequencing and single-nucleotide polymorphism array tests were performed. Next-generation sequencing revealed a heterozygous nonsense pathogenic variant in ATM, c.742C > T (p.Arg248Ter) inherited from the father. Single-nucleotide polymorphism array revealed a compound heterozygous CNV, arr[GRCh37] 11q22.3(10851766–108183226) × 1, 31460 bp (exons 24–40 deletion of ATM) inherited from the mother, which was validated by reverse transcription-polymerase chain reaction analysis (RT-PCR). We demonstrated that this variant (NM_000051.4:c.3403_6006del) generated a product of in-frame deletion of exon 24–40 of ATM (p.Ser1135_Gln2002del). Conclusions The compound heterozygosity for ATM variants involving a previously described pathogenic SNV and a novel CNV may be associated with the atypical clinical manifestations. This clinical report extends the genetic and phenotypic spectrum of ATM pathogenic variants in atypical ataxia-telangiectasia, thus making implementation of advanced analysis beyond the routine next-generation sequencing an important consideration in diagnosis and rehabilitation services for children with ataxia-telangiectasia.

The natural history of ataxia-telangiectasia (A-T): A systematic review

“…Of the 18246 cases, family history of A-T was reported in 1274 cases ( Table 2 ) and 142 cases (53 studies) had 199 illnesses or symptoms other than A-T in a relative ( Fig 3A ). 1279 cases (109 studies [ 15 , 53 , 65 , 71 , 72 , 78 , 87 , 88 , 95 , 99 – 101 , 109 , 110 , 115 , 118 – 221 ]) were the children of consanguineous relationships, and 186 cases (86 studies [ 23 , 33 , 41 , 50 , 54 , 62 , 63 , 65 , 71 , 74 , 84 , 88 , 95 , 111 , 116 , 142 , 146 , 151 – 153 , 188 , 208 – 210 , 212 , 214 , 216 , 218 , 219 , 221 – 277 ]) were reported as being born of non-consanguineous relationships.…”

“…The lowest gestation was reported as “< 30 weeks”. Birth weight was reported in 41 cases (34 studies [ 43 , 59 , 63 , 84 , 108 , 110 , 111 , 139 , 178 , 206 , 212 , 231 , 242 , 252 , 254 , 263 , 268 , 272 , 276 , 298 , 305 , 325 , 372 , 380 , 384 , 391 , 399 – 406 ]) with median (range) of 2.9.5 (1.32 to 4.08) kg.…”

“…62 cases (27 studies [ 33 , 38 , 41 , 49 , 53 , 55 , 72 , 118 , 120 , 123 , 139 , 143 , 186 , 208 , 212 , 213 , 338 , 358 , 366 , 368 , 372 , 388 , 392 , 519 , 528 , 683 , 684 ]) reported an abnormal EMG. The youngest age at which an abnormal EMG was reported was 4 years 0 months.…”

Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India

“…The matched transcript profile might be associated with the atypical manifestation of A-T phenotype. Lee et al reported an atypical A-T harbouring compound heterozygous variant in A-T manifested with normal serum AFP, mild atrophy, delayed development and oculomotor apraxia 60 . These reports indicate that hypomorphic mutations are indeed associated with attenuated A-T phenotype 8 , 61 , 62 .…”

Correction to: Compound heterozygous variants including a novel copy number variation in a child with atypical ataxia-telangiectasia: a case report

“…This error may have affected the interpretation of the results, and therefore, the figure was replaced with the earlier correct version. The original article [ 1 ] has been corrected.…”