Genotype-phenotype relationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.32 deletion.
Microdeletion 12p13.33, though very rare, is an emerging condition associated with variable phenotype including a specific speech delay sound disorder, labelled childhood apraxia of speech (CAS), intellectual disability (ID) and neurobehavioral problems. Here we report a de novo 2.3 Mb interstitial 12p13.33-p13.32 deletion in a 5 year-old child with mild ID, speech delay, microcephaly, muscular hypotonia, and joint laxity. In contrast to previously reported patients with 12p13.33 monosomy, our patient's interstitial deletion spans the 12p13.33-12p13.32 region with the distal breakpoint within intron 12 of CACNA1C. Phenotype-genotype comparison between our case, previously reported patients, and subjects with 12p13.33 deletions led us to propose that haploinsufficiency of CACNA1C may influence the variability of the patients' phenotype, since the gene resulted disrupted or entirely deleted in the majority of reported patients. In addition, phenotypic features such as microcephaly, muscular hypotonia, and joint laxity are mainly present in patients with monosomy of 12p13.33 extending to the 12p13.32 portion. A common region of ~300 kb, harbouring EFCAB4B and PARP11, is deleted in patients with microcephaly while a second region of ~700 kb, including TSPAN9 and PMTR8, could be associated with muscle hypotonia and joint laxity. These data reinforce the hypothesis that multiple haploinsufficient genes and age-dependent observation may concur to generate the variable phenotype associated with 12p13.33 deletion.
Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Ostuni, Brindisi, Italy.
Isabella
I
Fanizza
Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, Via Don Luigi Monza, 20, 23842 Bosisio Parini, Lecco, Italy.
Sara
S
Bertuzzo
Molecular Biology Laboratory, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
Silvana
S
Beri
Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Ostuni, Brindisi, Italy.
Elisabetta
E
Scalera
Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Ostuni, Brindisi, Italy.
Angelo
A
Massagli
Child Psychopathology Unit - Neuropsychology of Developmental Disorders, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
Maria Enrica
ME
Sali
Molecular Biology Laboratory, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
Roberto
R
Giorda
Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, Via Don Luigi Monza, 20, 23842 Bosisio Parini, Lecco, Italy. Electronic address: clara.bonaglia@bp.lnf.it.
Maria Clara
MC
Bonaglia
D001072:Apraxias / Q000235:genetics; D002675:Child, Preschool; D002872:Chromosome Deletion; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007593:Joint Instability / Q000235:genetics*; D007805:Language Development Disorders / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype
12p13.33 Deletion; Array-CGH; CACNA1C; Interstitial deletion; Microcephaly; Speech delay