Genotype-Phenotype Correlation in Cri du Chat Patients Carrying One or Two Copies of the TRIO Gene
10 affiliations
- 1Division of Paediatrics, Castelli Hospital, 28922 Verbania, Italy
- 2Scientific Committee of Associazione Bambini Cri du Chat (A.B.C.), 50026 Firenze, Italy
- 3Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
- 4Medical Genetics Unit, IRCCS San Matteo Foundation, 27100 Pavia, Italy
- 5Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
- 6Paediatrics Unit, Neuroscience, Mental Health and Sense Organs (NESMOS) Department, Faculty of Medicine and Psychology, Sapienza University of Roma, 00189 Roma, Italy
- 7Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- 8Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy
- 9Department of Brain and Behavior Neuroscience, University of Pavia, 27100 Pavia, Italy
- 10Department of Molecular Biotechnology and Science for Health, University of Torino, 10126 Torino, Italy
Abstract
Cri du Chat syndrome (CdCS) results from a variable-sized deletion of the short arm of chromosome 5 (5p) and is characterized by marked phenotypic heterogeneity. Previous genotype–phenotype correlation studies have primarily focused on deletion size, an approach inherently limited by the large number of genes within the deletion. A gene-centered strategy may therefore offer a better framework for interpreting specific clinical features. Among candidate genes on 5p, TRIO plays a critical role in RAC1-mediated neurodevelopment; furthermore, in related neurodevelopmental disorders, loss-of-function variants are associated with microcephaly, whereas gain-of-function variants are associated with macrocephaly. Clinical, cytogenetic, and molecular data were retrieved from the main database of the Italian charity A.B.C. (Associazione Bambini Cri du Chat). Fifty-two patients, classified as carriers of one or two copies of the TRIO gene, were included based on the availability of head circumference (HC) measurements, developmental milestones (sitting, walking, and first words) data, and a CGH array. All data were analyzed in relation to TRIO allele dosage, deletion size, and sex. All patients showed a reduced HC compared with reference curves. However, HC measurements were consistently higher in patients carrying two TRIO alleles versus those carrying only one. Deletion size did not correlate with HC or developmental milestones. Patients with two TRIO alleles generally achieved motor and language milestones earlier, and some differences between males and females, suggested the possibility of sex-specific differences. These findings indicate that TRIO allele dosage might contribute to head size and developmental outcomes in CdCS independent of deletion size. A gene-centered approach could thus improve genotype–phenotype correlations in chromosomal disorders and highlight the importance of considering sex-specific effects in clinical and rehabilitative management.
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BibTeX
@article{guala2026genotypephenotype,
title = {{Genotype-Phenotype Correlation in Cri du Chat Patients Carrying One or Two Copies of the TRIO Gene}},
author = {Andrea Guala and Fabio Tognon and Giuseppe Minniti and Fabio Sirchia and Silvia Kalantari and Michela Malacarne and Chiara Baldo and Alessandro Ferretti and Carla Liaci and Davide Politano and Roberto De Icco and Giorgio Roberto Merlo and Enza Maria Valente and Cesare Danesino},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219400},
url = {https://www.mdpi.com/1422-0067/27/21/9400},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Genotype-Phenotype Correlation in Cri du Chat Patients Carrying One or Two Copies of the TRIO Gene
AU - Andrea Guala
AU - Fabio Tognon
AU - Giuseppe Minniti
AU - Fabio Sirchia
AU - Silvia Kalantari
AU - Michela Malacarne
AU - Chiara Baldo
AU - Alessandro Ferretti
AU - Carla Liaci
AU - Davide Politano
AU - Roberto De Icco
AU - Giorgio Roberto Merlo
AU - Enza Maria Valente
AU - Cesare Danesino
PY - 2026
DA - 2026/10/22
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219400
UR - https://www.mdpi.com/1422-0067/27/21/9400
AB - Cri du Chat syndrome (CdCS) results from a variable-sized deletion of the short arm of chromosome 5 (5p) and is characterized by marked phenotypic heterogeneity. Previous genotype–phenotype correlation studies have primarily focused on deletion size, an approach inherently limited by the large number of genes within the deletion. A gene-centered strategy may therefore offer a better framework for interpreting specific clinical features. Among candidate genes on 5p, TRIO plays a critical role in RAC1-mediated neurodevelopment; furthermore, in related neurodevelopmental disorders, loss-of-function variants are associated with microcephaly, whereas gain-of-function variants are associated with macrocephaly. Clinical, cytogenetic, and molecular data were retrieved from the main database of the Italian charity A.B.C. (Associazione Bambini Cri du Chat). Fifty-two patients, classified as carriers of one or two copies of the TRIO gene, were included based on the availability of head circumference (HC) measurements, developmental milestones (sitting, walking, and first words) data, and a CGH array. All data were analyzed in relation to TRIO allele dosage, deletion size, and sex. All patients showed a reduced HC compared with reference curves. However, HC measurements were consistently higher in patients carrying two TRIO alleles versus those carrying only one. Deletion size did not correlate with HC or developmental milestones. Patients with two TRIO alleles generally achieved motor and language milestones earlier, and some differences between males and females, suggested the possibility of sex-specific differences. These findings indicate that TRIO allele dosage might contribute to head size and developmental outcomes in CdCS independent of deletion size. A gene-centered approach could thus improve genotype–phenotype correlations in chromosomal disorders and highlight the importance of considering sex-specific effects in clinical and rehabilitative management.
SN - 1422-0067
ER -