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Background <p>Phelan-McDermid syndrome (PMS) is caused in the majority of cases by the loss or mutation of one allele of the <i>SHANK3</i> gene, located in human chr 22q13.33. PMS displays large interindividual differences in clinical severity and longitudinal trajectory. Other genes located in this chromosomal region are known to contribute to the clinical phenotype (<i>CELSR1</i>, <i>TCF20</i>) in patients with larger deletions. The aim of this study is to identify clinically-relevant phenotypic features significantly influenced by the size of chromosome 22q terminal deletion and to identify new potential candidate genes likely to be involved in these phenotypic effects.</p> Methods <p>Genotype–phenotype correlations were investigated in 63 PMS patients directly ascertained by deep clinical phenotyping and determination of deletion size (Agilent CGH-array 180K or 400K). Patients were partitioned into eleven categories, based on deletion size (Mb). Phenotypic variables significantly influenced by deletion size were initially detected by exact χ<sup>2</sup> (10,000 iterations) and Kendall’s Tau. Candidate genes were then sought using: (a) ROC curves for binary dichotomous variables; (b) best separation threshold for quantitative variables.</p> Results <p>Phenotypic variables significantly associated with chromosome 22q deletion size in our sample include: expressive language (<i>p</i> &lt; 0.001); motor development timing (<i>p</i> &lt; 0.001); gait (<i>p</i> &lt; 0.001); muscle strength (<i>p</i> &lt; 0.01); social cognition, encompassing eye contact, exchange gesture, and joint attention (<i>p</i> &lt; 0.001—&lt; 0.05); infectious diseases coincident with the onset of behavioral manifestations (<i>p</i> &lt; 0.001); brain structural abnormalities on MRI (<i>p</i> &lt; 0.001); dysmorphisms (<i>p</i> &lt; 0.001); renal and urinary malformations (<i>p</i> &lt; 0.01); comorbid lifelong bipolar disorder (<i>p</i> &lt; 0.05). The best separation thresholds for many of these variables were located within or nearby genes playing important morphogenetic (<i>PLXNB2, TAFA5</i>) or neurodevelopmental roles (<i>BRD1</i>, <i>TBC1D22A</i>, <i>ATXN10</i> and/or <i>FBLN1</i>). For renal malformations, the two best thresholds point toward one long non-coding RNA and a cluster of antisense RNAs.</p> Conclusions <p>The genes identified in this study appear as strong candidates to contribute to the PMS phenotype, by conferring an additional layer of abnormal neurodevelopment and impaired morphogenesis to the disruptive effects produced by <i>SHANK3</i> haploinsufficiency.</p>

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Chromosome 22q13 terminal deletion size is associated with relevant clinical features in a sample of 63 Italian patients with Phelan-McDermid syndrome

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  • 发表日期：

    2026年5月26日

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  • Laura Sandoni,
  • Fethia Chehbani,
  • Lisa Asta,
  • Michela Camia,
  • Arianna Ricciardello,
  • Pasquale Tomaiuolo,
  • Francesca Cucinotta,
  • Laura Turriziani,
  • Maria Boncoddo,
  • Fabiana Bellomo,
  • Marco Baccarin,
  • Chiara Picinelli,
  • Paola Castronovo,
  • Roberto Sacco,
  • Carla Lintas,
  • Ignazio Stefano Piras,
  • Francesco Pelagatti,
  • Federico Banchelli,
  • Riccardo Cuoghi Costantini,
  • Roberto D’Amico,
  • Antonio M. Persico

摘要

Background

Phelan-McDermid syndrome (PMS) is caused in the majority of cases by the loss or mutation of one allele of the SHANK3 gene, located in human chr 22q13.33. PMS displays large interindividual differences in clinical severity and longitudinal trajectory. Other genes located in this chromosomal region are known to contribute to the clinical phenotype (CELSR1, TCF20) in patients with larger deletions. The aim of this study is to identify clinically-relevant phenotypic features significantly influenced by the size of chromosome 22q terminal deletion and to identify new potential candidate genes likely to be involved in these phenotypic effects.

Methods

Genotype–phenotype correlations were investigated in 63 PMS patients directly ascertained by deep clinical phenotyping and determination of deletion size (Agilent CGH-array 180K or 400K). Patients were partitioned into eleven categories, based on deletion size (Mb). Phenotypic variables significantly influenced by deletion size were initially detected by exact χ2 (10,000 iterations) and Kendall’s Tau. Candidate genes were then sought using: (a) ROC curves for binary dichotomous variables; (b) best separation threshold for quantitative variables.

Results

Phenotypic variables significantly associated with chromosome 22q deletion size in our sample include: expressive language (p < 0.001); motor development timing (p < 0.001); gait (p < 0.001); muscle strength (p < 0.01); social cognition, encompassing eye contact, exchange gesture, and joint attention (p < 0.001—< 0.05); infectious diseases coincident with the onset of behavioral manifestations (p < 0.001); brain structural abnormalities on MRI (p < 0.001); dysmorphisms (p < 0.001); renal and urinary malformations (p < 0.01); comorbid lifelong bipolar disorder (p < 0.05). The best separation thresholds for many of these variables were located within or nearby genes playing important morphogenetic (PLXNB2, TAFA5) or neurodevelopmental roles (BRD1, TBC1D22A, ATXN10 and/or FBLN1). For renal malformations, the two best thresholds point toward one long non-coding RNA and a cluster of antisense RNAs.

Conclusions

The genes identified in this study appear as strong candidates to contribute to the PMS phenotype, by conferring an additional layer of abnormal neurodevelopment and impaired morphogenesis to the disruptive effects produced by SHANK3 haploinsufficiency.