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Dystonia, facial dysmorphism, intellectual disability and breast cancer associated with a chromosome 13q34 duplication and overexpression of TFDP1: case report.

Moscovich M, LeDoux MS, Xiao J, Rampon GL, Vemula SR, Rodriguez RL, Foote KD, Okun MS - BMC Med. Genet. (2013)

Bottom Line: The 218,345 bp duplication was found to include ADPRHL1, DCUN1D2, and TMCO3, and a 69 bp fragment from a long terminal repeat (LTR) located within Intron 3 of TFDP1.No pathogenic mutations were identified in BRCA1 or BRCA2.Overexpression of TFDP1 has been associated with breast cancer and may also be linked to the tall stature, dysmorphism and dystonia seen in our patient.

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ABSTRACT

Background: Dystonia is a movement disorder characterized by involuntary sustained muscle contractions causing twisting and repetitive movements or abnormal postures. Some cases of primary and neurodegenerative dystonia have been associated with mutations in individual genes critical to the G1-S checkpoint pathway (THAP1, ATM, CIZ1 and TAF1). Secondary dystonia is also a relatively common clinical sign in many neurogenetic disorders. However, the contribution of structural variation in the genome to the etiopathogenesis of dystonia remains largely unexplored.

Case presentation: Cytogenetic analyses with the Affymetrix Genome-Wide Human SNP Array 6.0 identified a chromosome 13q34 duplication in a 36 year-old female with global developmental delay, facial dysmorphism, tall stature, breast cancer and dystonia, and her neurologically-normal father. Dystonia improved with bilateral globus pallidus interna (GPi) deep brain stimulation (DBS). Genomic breakpoint analysis, quantitative PCR (qPCR) and leukocyte gene expression were used to characterize the structural variant. The 218,345 bp duplication was found to include ADPRHL1, DCUN1D2, and TMCO3, and a 69 bp fragment from a long terminal repeat (LTR) located within Intron 3 of TFDP1. The 3' breakpoint was located within Exon 1 of a TFDP1 long non-coding RNA (NR_026580.1). In the affected subject and her father, gene expression was higher for all three genes located within the duplication. However, in comparison to her father, mother and neurologically-normal controls, the affected subject also showed marked overexpression (2×) of the transcription factor TFDP1 (NM_007111.4). Whole-exome sequencing identified an SGCE variant (c.1295G > A, p.Ser432His) that could possibly have contributed to the development of dystonia in the proband. No pathogenic mutations were identified in BRCA1 or BRCA2.

Conclusion: Overexpression of TFDP1 has been associated with breast cancer and may also be linked to the tall stature, dysmorphism and dystonia seen in our patient.

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Related in: MedlinePlus

Frontal (A) and lateral (B) photographs 4 months after GPi DBS show the presence of mild facial dystonia and dysmorphic features. C) Arachnodactyl and hirsutism. D) Virtual resolution of facial dystonia 2 yrs after GPi DBS.
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Figure 1: Frontal (A) and lateral (B) photographs 4 months after GPi DBS show the presence of mild facial dystonia and dysmorphic features. C) Arachnodactyl and hirsutism. D) Virtual resolution of facial dystonia 2 yrs after GPi DBS.

Mentions: At age 36, general physical examination revealed facial dysmorphism with hypertelorism, down slanting palpebral fissures, mild ptosis and large low-set ears with mild posterior rotation (Figure 1). Other clinical features included hirsutism, low anterior hairline, micrognathia, brevicollis, scoliosis, arachnodactyly, tall stature (182.9 cm), and a weight of 62.3 kg (body mass index = 18.6). On neurological examination, she was moderately inattentive. No primitive reflexes were noted. She scored a 19/30 on the Montreal Cognitive Assessment (MoCA). MoCA scores of 26 and higher are considered normal. Although cranial nerves were all normal, speech was mildly dysarthric, and facial dystonia was overt. Muscle strength testing was normal. There was no focal atrophy or fasciculations. There was no obvious upper extremity ataxia although testing of coordination was limited by the presence of dystonia. Gait was broad-based and ataxic, and she required assistance to walk. Walking was also compromised by dystonic posturing of her trunk and arms. Sensory testing was normal. Cervical dystonia was manifest as severe retrocollis. Truncal and bilateral arm dystonia had a clear action component and worsened during movement, particularly walking. No contractures were present in the arms or legs. A score of 37 was recorded for the pre-operative Unified Dystonia Rating Scale (UDRS, maximum score is 112).


Dystonia, facial dysmorphism, intellectual disability and breast cancer associated with a chromosome 13q34 duplication and overexpression of TFDP1: case report.

Moscovich M, LeDoux MS, Xiao J, Rampon GL, Vemula SR, Rodriguez RL, Foote KD, Okun MS - BMC Med. Genet. (2013)

Frontal (A) and lateral (B) photographs 4 months after GPi DBS show the presence of mild facial dystonia and dysmorphic features. C) Arachnodactyl and hirsutism. D) Virtual resolution of facial dystonia 2 yrs after GPi DBS.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3722009&req=5

Figure 1: Frontal (A) and lateral (B) photographs 4 months after GPi DBS show the presence of mild facial dystonia and dysmorphic features. C) Arachnodactyl and hirsutism. D) Virtual resolution of facial dystonia 2 yrs after GPi DBS.
Mentions: At age 36, general physical examination revealed facial dysmorphism with hypertelorism, down slanting palpebral fissures, mild ptosis and large low-set ears with mild posterior rotation (Figure 1). Other clinical features included hirsutism, low anterior hairline, micrognathia, brevicollis, scoliosis, arachnodactyly, tall stature (182.9 cm), and a weight of 62.3 kg (body mass index = 18.6). On neurological examination, she was moderately inattentive. No primitive reflexes were noted. She scored a 19/30 on the Montreal Cognitive Assessment (MoCA). MoCA scores of 26 and higher are considered normal. Although cranial nerves were all normal, speech was mildly dysarthric, and facial dystonia was overt. Muscle strength testing was normal. There was no focal atrophy or fasciculations. There was no obvious upper extremity ataxia although testing of coordination was limited by the presence of dystonia. Gait was broad-based and ataxic, and she required assistance to walk. Walking was also compromised by dystonic posturing of her trunk and arms. Sensory testing was normal. Cervical dystonia was manifest as severe retrocollis. Truncal and bilateral arm dystonia had a clear action component and worsened during movement, particularly walking. No contractures were present in the arms or legs. A score of 37 was recorded for the pre-operative Unified Dystonia Rating Scale (UDRS, maximum score is 112).

Bottom Line: The 218,345 bp duplication was found to include ADPRHL1, DCUN1D2, and TMCO3, and a 69 bp fragment from a long terminal repeat (LTR) located within Intron 3 of TFDP1.No pathogenic mutations were identified in BRCA1 or BRCA2.Overexpression of TFDP1 has been associated with breast cancer and may also be linked to the tall stature, dysmorphism and dystonia seen in our patient.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Dystonia is a movement disorder characterized by involuntary sustained muscle contractions causing twisting and repetitive movements or abnormal postures. Some cases of primary and neurodegenerative dystonia have been associated with mutations in individual genes critical to the G1-S checkpoint pathway (THAP1, ATM, CIZ1 and TAF1). Secondary dystonia is also a relatively common clinical sign in many neurogenetic disorders. However, the contribution of structural variation in the genome to the etiopathogenesis of dystonia remains largely unexplored.

Case presentation: Cytogenetic analyses with the Affymetrix Genome-Wide Human SNP Array 6.0 identified a chromosome 13q34 duplication in a 36 year-old female with global developmental delay, facial dysmorphism, tall stature, breast cancer and dystonia, and her neurologically-normal father. Dystonia improved with bilateral globus pallidus interna (GPi) deep brain stimulation (DBS). Genomic breakpoint analysis, quantitative PCR (qPCR) and leukocyte gene expression were used to characterize the structural variant. The 218,345 bp duplication was found to include ADPRHL1, DCUN1D2, and TMCO3, and a 69 bp fragment from a long terminal repeat (LTR) located within Intron 3 of TFDP1. The 3' breakpoint was located within Exon 1 of a TFDP1 long non-coding RNA (NR_026580.1). In the affected subject and her father, gene expression was higher for all three genes located within the duplication. However, in comparison to her father, mother and neurologically-normal controls, the affected subject also showed marked overexpression (2×) of the transcription factor TFDP1 (NM_007111.4). Whole-exome sequencing identified an SGCE variant (c.1295G > A, p.Ser432His) that could possibly have contributed to the development of dystonia in the proband. No pathogenic mutations were identified in BRCA1 or BRCA2.

Conclusion: Overexpression of TFDP1 has been associated with breast cancer and may also be linked to the tall stature, dysmorphism and dystonia seen in our patient.

Show MeSH
Related in: MedlinePlus