12p13.33 microdeletion including ELKS/ERC1, a new locus associated with childhood apraxia of speech

Speech sound disorders are heterogeneous conditions, and sporadic and familial cases have been described. However, monogenic inheritance explains only a small proportion of such disorders, in particular in cases with childhood apraxia of speech (CAS). Deletions of <5 Mb involving the 12p13.33 locus is one of the least commonly deleted subtelomeric regions. Only four patients have been reported with such a deletion diagnosed with fluorescence in situ hybridisation telomere analysis or array CGH. To further delineate this rare microdeletional syndrome, a French collaboration together with a search in the Decipher database allowed us to gather nine new patients with a 12p13.33 subtelomeric or interstitial rearrangement identified by array CGH. Speech delay was found in all patients, which could be defined as CAS when patients had been evaluated by a speech therapist (5/9 patients). Intellectual deficiency was found in 5/9 patients only, and often associated with psychiatric manifestations of various severity. Two such deletions were inherited from an apparently healthy parent, but reevaluation revealed abnormal speech production at least in childhood, suggesting variable expressivity. The ELKS/ERC1 gene, which encodes for a synaptic factor, is found in the smallest region of overlap. These results reinforce the hypothesis that deletions of the 12p13.33 locus may be responsible for variable phenotypes including CAS associated with neurobehavioural troubles and that the presence of CAS justifies a genetic work-up.

[1]  D. Drayna,et al.  Genetics of speech and language disorders. , 2011, Annual review of genomics and human genetics.

[2]  Wendy Roberts,et al.  Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. , 2006, American journal of human genetics.

[3]  D. Bishop Which Neurodevelopmental Disorders Get Researched and Why? , 2010, PloS one.

[4]  Marie-Noëlle Metz-Lutz,et al.  SRPX2 mutations in disorders of language cortex and cognition. , 2006, Human molecular genetics.

[5]  K Mathiak,et al.  Effects of a CACNA1C genotype on attention networks in healthy individuals , 2010, Psychological Medicine.

[6]  Yamato Hida,et al.  CAST and ELKS proteins: structural and functional determinants of the presynaptic active zone. , 2010, Journal of biochemistry.

[7]  Stephen W. Scherer,et al.  Speech and Language Impairment and Oromotor Dyspraxia Due to Deletion of 7 q 31 That Involves FOXP 2 , 2006 .

[8]  A. Mohn,et al.  Mosaic 7q31 Deletion Involving FOXP2 Gene Associated With Language Impairment , 2012, Pediatrics.

[9]  C. Chapman,et al.  Partial monosomy 12p13.1----13.3. , 1987, Journal of medical genetics.

[10]  Valeur diagnostique de ERTL4: un test de repérage des troubles du langage chez l'enfant de 4 ans , 1998 .

[11]  M. Mishkin,et al.  FOXP2 and the neuroanatomy of speech and language , 2005, Nature Reviews Neuroscience.

[12]  Constance Scharff,et al.  FOXP2 as a molecular window into speech and language. , 2009, Trends in genetics : TIG.

[13]  William B Dobyns,et al.  Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency , 2010, European Journal of Human Genetics.

[14]  J. Tomblin,et al.  Prevalence of specific language impairment in kindergarten children. , 1997, Journal of speech, language, and hearing research : JSLHR.

[15]  Andrew Spencer,et al.  A 785kb deletion of 3p14.1p13, including the FOXP1 gene, associated with speech delay, contractures, hypertonia and blepharophimosis. , 2009, European journal of medical genetics.

[16]  Karen Forrest,et al.  Diagnostic criteria of developmental apraxia of speech used by clinical speech-language pathologists. , 2003, American journal of speech-language pathology.

[17]  N. Sykes,et al.  Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. , 2005, American journal of human genetics.

[18]  A. Macdonald,et al.  Subtelomeric deletion of 12p: Description of a third case and review , 2010, American journal of medical genetics. Part A.

[19]  J. Kivlin,et al.  Phenotypic variation in the del(12p) syndrome. , 1985, American journal of medical genetics.

[20]  Jay Shendure,et al.  Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations , 2012, Nature Genetics.

[21]  T. de Ravel,et al.  Subtelomeric imbalances in phenotypically normal individuals , 2007, Human mutation.

[22]  M. Holder,et al.  Delineation of 15q13.3 microdeletions , 2010, Clinical genetics.

[23]  Jessica Brian,et al.  Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2 , 2006, American journal of medical genetics. Part A.

[24]  M C O'Donovan,et al.  The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia , 2009, Molecular Psychiatry.

[25]  D. Bittel,et al.  1.39 Mb inherited interstitial deletion in 12p13.33 associated with developmental delay. , 2011, European journal of medical genetics.

[26]  Dorothy V. M. Bishop,et al.  Genetic influences on language impairment and phonological short-term memory , 2005, Trends in Cognitive Sciences.

[27]  Xavier Estivill,et al.  Comprehensive copy number variant (CNV) analysis of neuronal pathways genes in psychiatric disorders identifies rare variants within patients. , 2010, Journal of psychiatric research.

[28]  D. Geschwind,et al.  A functional genetic link between distinct developmental language disorders. , 2008, The New England journal of medicine.

[29]  J. Duffy,et al.  Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2. , 2006, Journal of speech, language, and hearing research : JSLHR.

[30]  Erik Meijering,et al.  Rab6, Rab8, and MICAL3 Cooperate in Controlling Docking and Fusion of Exocytotic Carriers , 2011, Current Biology.

[31]  Masahiko Watanabe,et al.  SynArfGEF is a guanine nucleotide exchange factor for Arf6 and localizes preferentially at post‐synaptic specializations of inhibitory synapses , 2011, Journal of neurochemistry.

[32]  M. Craen,et al.  Short arm deletion of chromosome 12 , 1975, Humangenetik.

[33]  D. Ledbetter,et al.  Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities , 2005, Journal of Medical Genetics.

[34]  A. Forabosco,et al.  Distal 12p deletion in a stillborn infant. , 1990, American journal of medical genetics.

[35]  C. Rooryck,et al.  2.3 Mb terminal deletion in 12p13.33 associated with oculoauriculovertebral spectrum and evaluation of WNT5B as a candidate gene. , 2009, European journal of medical genetics.

[36]  L. Hinton,et al.  A familial cryptic subtelomeric deletion 12p with variable phenotypic effect , 2002, Clinical genetics.

[37]  Y. Akimoto,et al.  ELKS, a protein structurally related to the active zone-associated protein CAST, is expressed in pancreatic beta cells and functions in insulin exocytosis: interaction of ELKS with exocytotic machinery analyzed by total internal reflection fluorescence microscopy. , 2005, Molecular biology of the cell.

[38]  F. Guillemin,et al.  [Diagnostic value of ERTL4: a screening test of language disorders in 4-year-old children]. , 1998, Archives de pediatrie : organe officiel de la Societe francaise de pediatrie.

[39]  Gina Conti-Ramsden,et al.  The prevalence of autistic spectrum disorders in adolescents with a history of specific language impairment (SLI). , 2006, Journal of child psychology and psychiatry, and allied disciplines.

[40]  A. Monaco,et al.  A forkhead-domain gene is mutated in a severe speech and language disorder , 2001, Nature.

[41]  L. Black,et al.  The Hypothesis of Apraxia of Speech in Children with Autism Spectrum Disorder , 2011, Journal of autism and developmental disorders.

[42]  D. Mechanic,et al.  The concept of illness behaviour: culture, situation and personal predisposition , 1986, Psychological Medicine.

[43]  E. Fombonne,et al.  De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. , 2010, American journal of human genetics.