Absence of a Paternally Inherited FOXP2 Gene in Developmental Verbal Dyspraxia
2006; Elsevier BV; Volume: 79; Issue: 5 Linguagem: Inglês
10.1086/508902
ISSN1537-6605
AutoresLars Feuk, Aino Kalervo, Marita Lipsanen‐Nyman, Jennifer Skaug, Kazuhiko Nakabayashi, Brenda Finucane, Danielle Hartung, A. Micheil Innes, Batsheva Kerem, Małgorzata J.M. Nowaczyk, Joseph Rivlin, Wendy Roberts, Lili Senman, Anne Summers, Peter Szatmari, Virginia Wong, John B. Vincent, Susan Zeesman, Lucy R. Osborne, Janis Oram Cardy, Juha Kere, Stephen W. Scherer, Katariina Hannula-Jouppi,
Tópico(s)Genetics and Neurodevelopmental Disorders
ResumoMutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD—5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development. Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD—5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development. Forkhead-box P2 (FOXP2) was the first gene discovered to be involved in speech and language disorder, through genetic mapping and mutational analysis in a three-generation pedigree (referred to as the "KE" family) with an autosomal dominant form of the condition.1Lai CS Fisher SE Hurst JA Levy ER Hodgson S Fox M Jeremiah S Povey S Jamison DC Green ED Vargha-Khadem F Monaco AP The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder.Am J Hum Genet. 2000; 67: 357-368Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 2Lai CS Fisher SE Hurst JA Vargha-Khadem F Monaco AP A forkhead-domain gene is mutated in a severe speech and language disorder.Nature. 2001; 413: 519-523Crossref PubMed Scopus (1303) Google Scholar, 3Hurst JA Baraitser M Auger E Graham F Norell S An extended family with a dominantly inherited speech disorder.Dev Med Child Neurol. 1990; 32: 352-355Crossref PubMed Scopus (226) Google Scholar Characterization of a translocation breakpoint in a patient (called "CS") with a similar clinical presentation added further support.2Lai CS Fisher SE Hurst JA Vargha-Khadem F Monaco AP A forkhead-domain gene is mutated in a severe speech and language disorder.Nature. 2001; 413: 519-523Crossref PubMed Scopus (1303) Google Scholar The KE phenotype is described as severe developmental verbal apraxia with impairment in both expressive and receptive language skills,3Hurst JA Baraitser M Auger E Graham F Norell S An extended family with a dominantly inherited speech disorder.Dev Med Child Neurol. 1990; 32: 352-355Crossref PubMed Scopus (226) Google Scholar categorized as developmental verbal dyspraxia (DVD [MIM 602081]). Disruption of both copies of Foxp2 in mice causes severe motor impairment, premature death, and absence of ultrasonic vocalizations normally elicited when pups are separated from their mothers.4Shu W Cho JY Jiang Y Zhang M Weisz D Elder GA Schmeidler J De Gasperi R Sosa MA Rabidou D Santucci AC Perl D Morrisey E Buxbaum JD Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene.Proc Natl Acad Sci USA. 2005; 102: 9643-9648Crossref PubMed Scopus (288) Google Scholar In the heterozygous-knockout mice, there is modest developmental delay but a significant alteration in ultrasonic vocalizations. The FOXP2 protein is an evolutionarily conserved transcriptional repressor containing a zinc-finger motif, a forkhead DNA-binding domain, and a polyglutamine tract.5Bruce HA Margolis RL FOXP2: novel exons, splice variants, and CAG repeat length stability.Hum Genet. 2002; 111: 136-144Crossref PubMed Scopus (67) Google Scholar There are several isoforms of the gene, with the longest characterized transcript encompassing 25 exons spanning >600 kb of DNA (fig. 1)5Bruce HA Margolis RL FOXP2: novel exons, splice variants, and CAG repeat length stability.Hum Genet. 2002; 111: 136-144Crossref PubMed Scopus (67) Google Scholar; the gene is expressed in a wide range of tissues throughout development. On the basis of structural and functional studies in the KE family, FOXP2 has been suggested to be involved in the development of brain regions affecting motor control and neural structures that mediate speech and language.6Lai CS Gerrelli D Monaco AP Fisher SE Copp AJ FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder.Brain. 2003; 126: 2455-2462Crossref PubMed Scopus (266) Google Scholar The KE family carries a heterozygous point mutation in exon 14 (amino acid 553, resulting in an arginine-to-histidine change) of the FOXP2 consensus. Transmission of mutated FOXP2 is maternal, except in one case of paternal transmission.3Hurst JA Baraitser M Auger E Graham F Norell S An extended family with a dominantly inherited speech disorder.Dev Med Child Neurol. 1990; 32: 352-355Crossref PubMed Scopus (226) Google Scholar The chromosome 7 translocation breakpoint (parental origin not described) in CS occurs between exons 3b and 4, disrupting all known isoforms of FOXP2. Recently, a screen for FOXP2 mutations in 49 probands with verbal dyspraxia as their primary phenotype detected a maternally inherited nonsense mutation yielding a truncated protein in one family, as well as two putative missense mutations in two other patients.7MacDermot KD Bonora E Sykes N Coupe AM Lai CS Vernes SC Vargha-Khadem F McKenzie F Smith RL Monaco AP Fisher SE Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits.Am J Hum Genet. 2005; 76: 1074-1080Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar These findings suggest that FOXP2 mutations are a relatively rare cause for speech and language impairment. The distinctive clinical presentation of the KE family8Vargha-Khadem F Gadian DG Copp A Mishkin M FOXP2 and the neuroanatomy of speech and language.Nat Rev Neurosci. 2005; 6: 131-138Crossref PubMed Scopus (299) Google Scholar has served as a reference for us to identify patients with a similar phenotype. In addition, we have been collecting patients with chromosomal anomalies affecting chromosome 7,9Scherer SW Cheung J MacDonald JR Osborne LR Nakabayashi K Herbrick JA Carson AR et al.Human chromosome 7: DNA sequence and biology.Science. 2003; 300: 767-772Crossref PubMed Scopus (158) Google Scholar with a specific focus on patients with an affected FOXP2 locus. Thus, patients have been ascertained both via genotype and via phenotype. A specific subgroup of patients displaying DVD (in addition to other phenotypic characteristics) includes patients with maternal uniparental disomy (UPD) of chromosome 7 (matUPD7). We hypothesized that this can be attributed to FOXP2 and that there may be a parent-of-origin effect involved in FOXP2 regulation. The aim of this article is to describe the genetic and phenotypic similarities among patients exhibiting DVD, with FOXP2 as a main focus. We characterized 22 samples in this study. In this article, we describe 13 individuals with DVD who can be divided into groups on the basis of their genetic characteristics (table 1)—namely, group A, consisting of 5 individuals with 7q31 deletions of FOXP2 on the paternally inherited chromosome; group B, consisting of 1 individual with a 7q31 translocation interrupting FOXP2; and group C, consisting of 7 patients with matUPD7. Table 1 also describes nine individuals without DVD. Group D includes two patients, one with with partial matUPD7 and one with a deletion, with rearrangements starting downstream of FOXP2; group E includes two patients with paternal UPD7 (patUPD7); and group F has five patients with FOXP2 deletions (on the paternally derived chromosome) and a more complex global developmental delay, including speech and language disorder.Table 1Summary of 22 Individuals with or without DVDPresence of TraitcPlus (+) indicates positive scoring on this trait, and minus (−) indicates negative scoring. NR = not recorded. IQ = intelligence quotient.Group and Patient (Alias and Reference)aLiterature and database searches revealed another 16 patients (not shown) whose karyotypes suggest deletion of FOXP2, but no molecular or parent-of-origin data are available. Moreover, most of these patients were described as infants, and a specific language phenotype was therefore not included. Additional details for these samples and for those described in the table can be found at the Chromosome 7 Annotation Project Web site. We note that we do not see any neutral copy-number variants in the FOXP2 region (see the Database of Genomic Variants10).Karyotype (Deletion Size or Parental Source)bFor patients with UPD, the source of parental chromosomes—isodisomic (iso), heterodisomic (hetero), or both—is shown, if known.Late TalkingOromotor/ Verbal DyspraxiaArticulation DisorderReceptive Language ImpairmentExpressive Language ImpairmentSpeech TherapyBelow-Average Nonverbal/ Performance IQGross- and/or Fine- Motor DelaysPhenotypedThe final phenotype, as decided by multidisciplinary assessment, is shown. DD = developmental delay. CF = cystic fibrosis. CLD = congenital chloride diarrhea. Specific phenotypic details for any patients are available on request.Reference: KE2Lai CS Fisher SE Hurst JA Vargha-Khadem F Monaco AP A forkhead-domain gene is mutated in a severe speech and language disorder.Nature. 2001; 413: 519-523Crossref PubMed Scopus (1303) Google ScholarPoint mutation+++++++/−−DVD CS2Lai CS Fisher SE Hurst JA Vargha-Khadem F Monaco AP A forkhead-domain gene is mutated in a severe speech and language disorder.Nature. 2001; 413: 519-523Crossref PubMed Scopus (1303) Google Scholart(5;7)(q22q31.2)+++++NR−+DVDA: 1 (13772)46,XX,del(7)(q31.1q31.3)pat (15 Mb)++++++++DVD and DD 2 (27162)46,XX,del(7)(q31.2q32)pat (13 Mb)++++++++DVD 3 (24784)46,XY,del(7)(q31.1q31.3)pat (11 Mb)++++++−+DVD and ASD 4 (13583)11Zeesman S Nowaczyk MJ Teshima I Roberts W Cardy JO Brian J Senman L Feuk L Osborne LR Scherer SW Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2.Am J Med Genet A. 2006; 140: 509-514Crossref PubMed Scopus (98) Google Scholar46,XX,del(7)(q31.2q32.3)pat (15 Mb)++++++−+DVD and ASD-like 5 (33466)46,XX,del(7)(q22q31.3)pat (15 Mb)+++++++NRDVD and DDB: 6 (28577)46,XX,t(3;7)(q23q31.2)++++++NR+DVDC: 712Hannula K Kere J Pirinen S Holmberg C Lipsanen-Nyman M Do patients with maternal uniparental disomy for chromosome 7 have a distinct mild Silver-Russell phenotype?.J Med Genet. 2001; 38: 273-278Crossref PubMed Google Scholar46,XY,matUPD7 (iso)+++−++−+DVD and SRS 812Hannula K Kere J Pirinen S Holmberg C Lipsanen-Nyman M Do patients with maternal uniparental disomy for chromosome 7 have a distinct mild Silver-Russell phenotype?.J Med Genet. 2001; 38: 273-278Crossref PubMed Google Scholar46,XY,matUPD7 (iso/hetero)+NR+−−+NRNRDVD and SRS 912Hannula K Kere J Pirinen S Holmberg C Lipsanen-Nyman M Do patients with maternal uniparental disomy for chromosome 7 have a distinct mild Silver-Russell phenotype?.J Med Genet. 2001; 38: 273-278Crossref PubMed Google Scholar46,XX,matUPD7 (iso/hetero)+++−++NR−DVD and SRS 1012Hannula K Kere J Pirinen S Holmberg C Lipsanen-Nyman M Do patients with maternal uniparental disomy for chromosome 7 have a distinct mild Silver-Russell phenotype?.J Med Genet. 2001; 38: 273-278Crossref PubMed Google Scholar46,XX,matUPD7 (iso/hetero)+−+NR−+NR+DVD and SRS 1113Hannula K Lipsanen-Nyman M Kristo P Kaitila I Simola KO Lenko HL Tapanainen P Holmberg C Kere J Genetic screening for maternal uniparental disomy of chromosome 7 in prenatal and postnatal growth retardation of unknown cause.Pediatrics. 2002; 109: 441-448Crossref PubMed Scopus (35) Google Scholar46,XX,matUPD7 (iso)+NR+NRNR++−DVD and SRS 12 (LGL12989)46,XX,matUPD7 (iso)+NR++++NR+DVD and SRS 13 (27297)46,XY,matUPD7 (iso)++++++++DVD, SRS, and ASDDeRepresentative patients with chromosome 7 aberrations, FOXP2 intact, and no DVD.: 14 (C70001-3)46,XY,del(7)(q31.2q32.3)pat (15 Mb)+−−+++++DD 1514Hannula K Lipsanen-Nyman M Kontiokari T Kere J A narrow segment of maternal uniparental disomy of chromosome 7q31-qter in Silver-Russell syndrome delimits a candidate gene region.Am J Hum Genet. 2001; 68: 247-253Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar46,XX,matUPD7q31-qter (iso)−−−−−−−−SRSE: 1615Hoglund P Holmberg C de la Chapelle A Kere J Paternal isodisomy for chromosome 7 is compatible with normal growth and development in a patient with congenital chloride diarrhea.Am J Hum Genet. 1994; 55: 747-752PubMed Google Scholar46,XX,patUPD7 (iso)−−−−−−−−CLD 17 (18406)46,XY,patUPD7 (unknown)+−−−−+++DD and CFFfPatients with paternally inherited FOXP2 deletions but with incomplete clinical information or too complex a phenotype for the proper assessment of DVD.: 18 (23145)46,XY,del(7)(q31.2q32)pat (26 Mb)NRNRNRNRNRNR++DD, no speech, and ASD 19 (6635)46,XY,del(7)(q22q31.33)pat (22 Mb)NRNRNRNRNRNRNRNRNR 20 (10203)46,XX,del(7)(q31.2q32.2)pat (14 Mb)++NRNRNRNR−+DD 21 (11912)46,XX,del(7)(q31.1q33)pat (30 Mb)NRNRNRNRNRNR++DD and no speech 22 (31065)46,XY,del(7)(q31.2q32)pat (21 Mb)NRNRNRNRNRNR++DD and no speecha Literature and database searches revealed another 16 patients (not shown) whose karyotypes suggest deletion of FOXP2, but no molecular or parent-of-origin data are available. Moreover, most of these patients were described as infants, and a specific language phenotype was therefore not included. Additional details for these samples and for those described in the table can be found at the Chromosome 7 Annotation Project Web site. We note that we do not see any neutral copy-number variants in the FOXP2 region (see the Database of Genomic Variants10Iafrate AJ Feuk L Rivera MN Listewnik ML Donahoe PK Qi Y Scherer SW Lee C Detection of large-scale variation in the human genome.Nat Genet. 2004; 36: 949-951Crossref PubMed Scopus (2231) Google Scholar).b For patients with UPD, the source of parental chromosomes—isodisomic (iso), heterodisomic (hetero), or both—is shown, if known.c Plus (+) indicates positive scoring on this trait, and minus (−) indicates negative scoring. NR = not recorded. IQ = intelligence quotient.d The final phenotype, as decided by multidisciplinary assessment, is shown. DD = developmental delay. CF = cystic fibrosis. CLD = congenital chloride diarrhea. Specific phenotypic details for any patients are available on request.e Representative patients with chromosome 7 aberrations, FOXP2 intact, and no DVD.f Patients with paternally inherited FOXP2 deletions but with incomplete clinical information or too complex a phenotype for the proper assessment of DVD. Open table in a new tab The patients with matUPD7 have also received diagnoses of Silver-Russell Syndrome (SRS [MIM 180860]), a condition characterized by intrauterine growth retardation, postnatal short stature, and a characteristic, small triangular face. Dysmorphic features such as fifth-finger clinodactyly and skeletal asymmetry are also common in patients with SRS but are not required for diagnosis. Approximately 10% of patients with SRS have matUPD7.13Hannula K Lipsanen-Nyman M Kristo P Kaitila I Simola KO Lenko HL Tapanainen P Holmberg C Kere J Genetic screening for maternal uniparental disomy of chromosome 7 in prenatal and postnatal growth retardation of unknown cause.Pediatrics. 2002; 109: 441-448Crossref PubMed Scopus (35) Google Scholar, 16Kotzot D Schmitt S Bernasconi F Robinson WP Lurie IW Ilyina H Mehes K Hamel BC Otten BJ Hergersberg M Werder E Schoenle E Schinzel A Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation.Hum Mol Genet. 1995; 4: 583-587Crossref PubMed Scopus (247) Google Scholar, 17Nakabayashi K Fernandez BA Teshima I Shuman C Proud VK Curry CJ Chitayat D Grebe T Ming J Oshimura M Meguro M Mitsuya K Deb-Rinker P Herbrick JA Weksberg R Scherer SW Molecular genetic studies of human chromosome 7 in Russell-Silver syndrome.Genomics. 2002; 79: 186-196Crossref PubMed Scopus (32) Google Scholar Whereas DVD is not a frequent symptom in patients with SRS in general, it is commonly found in the subgroup of patients with matUPD7.12Hannula K Kere J Pirinen S Holmberg C Lipsanen-Nyman M Do patients with maternal uniparental disomy for chromosome 7 have a distinct mild Silver-Russell phenotype?.J Med Genet. 2001; 38: 273-278Crossref PubMed Google Scholar PatUPD7 has no apparent effect on growth and development, indicating that an imprinted gene on chromosome 7 may be involved in causing SRS.12Hannula K Kere J Pirinen S Holmberg C Lipsanen-Nyman M Do patients with maternal uniparental disomy for chromosome 7 have a distinct mild Silver-Russell phenotype?.J Med Genet. 2001; 38: 273-278Crossref PubMed Google Scholar, 18Hitchins MP Stanier P Preece MA Moore GE Silver-Russell syndrome: a dissection of the genetic aetiology and candidate chromosomal regions.J Med Genet. 2001; 38: 810-819Crossref PubMed Scopus (84) Google Scholar All individuals described in groups A, B, and C in table 1 had normal hearing. One of us (J.O.C.) had previously studied the prototypic KE family, which allowed direct comparisons of clinical descriptions to be made. Blood samples were collected and lymphoblast cell lines were established from a subset of the patients and their parents. The study was approved by the ethical review board of each hospital involved in this study. All patients and their families gave written consent. Karyotyping was performed on blood from all patients and, for the parents of patients with deletions, by analysis of G-banded metaphase chromosomes from cultured peripheral blood lymphocytes (table 1 and fig. 1). All parental karyotypes were normal, indicating that deletions were de novo. The site and/or extent of the chromosomal rearrangement(s) or UPDs and inheritance patterns were determined using a combination of genotyping, array comparative genomic hybridization, and FISH. One patient (patient 6) carried a translocation interrupting the FOXP2 gene. To our knowledge, only two patients with a translocation or inversion breakpoint within FOXP2 have been described elsewhere.2Lai CS Fisher SE Hurst JA Vargha-Khadem F Monaco AP A forkhead-domain gene is mutated in a severe speech and language disorder.Nature. 2001; 413: 519-523Crossref PubMed Scopus (1303) Google Scholar, 19Shriberg LD Ballard KJ Tomblin JB Duffy JR Odell KH Williams CA Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2.J Speech Lang Hear Res. 2006; 49: 500-525Crossref PubMed Scopus (112) Google Scholar The translocation breakpoint in patient 6 is localized to the intron between the first two 5′ UTR exons (s1 and s2) (fig. 1) of the longest known isoform of FOXP2 (not characterized in the original mutation study). Parental samples were not available for analysis. As summarized above, we observed that the remaining 12 individuals with confirmed DVD (5 with deletions and 7 with matUPD7) for whom inheritance could be established failed to have a paternally inherited FOXP2 gene. In contrast, patient 14, with an interstitial 7q31.2-q32.3 deletion starting just telomeric of FOXP2 (but leaving it intact), and patient 15, with partial matUPD7 (matUPD7q31-qter) (fig. 1)14Hannula K Lipsanen-Nyman M Kontiokari T Kere J A narrow segment of maternal uniparental disomy of chromosome 7q31-qter in Silver-Russell syndrome delimits a candidate gene region.Am J Hum Genet. 2001; 68: 247-253Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar and both parental copies of FOXP2, did not exhibit any characteristics of DVD. In group E (patients 16 and 17), absence of maternally inherited alleles in patUPD7 also does not lead to DVD. Patient 16, affected with recessive congenital chloride diarrhea,15Hoglund P Holmberg C de la Chapelle A Kere J Paternal isodisomy for chromosome 7 is compatible with normal growth and development in a patient with congenital chloride diarrhea.Am J Hum Genet. 1994; 55: 747-752PubMed Google Scholar had normal psychomotor and speech development without any articulation difficulties. Patient 17 (a patient with cystic fibrosis) had mild language delay, but this was likely due to general developmental delay, and he did not exhibit verbal dyspraxia. No data from either our current study or the literature yet document a maternal deletion of FOXP2; however, one maternally inherited translocation interrupting FOXP2 has been described.19Shriberg LD Ballard KJ Tomblin JB Duffy JR Odell KH Williams CA Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2.J Speech Lang Hear Res. 2006; 49: 500-525Crossref PubMed Scopus (112) Google Scholar These observations suggest a role for differential parental regulation of FOXP2 expression and lead us to reconsider possible mechanisms of FOXP2 activity in the pathophysiology of DVD and in normal development. Patients with an interstitial deletion encompassing FOXP2 (patients 1–5) (table 1) as well as with the t(3;7)(q23;q31.2) translocation interrupting FOXP2 (patient 6) all have a more severe form of DVD compared with the KE family members. Data on the patients' speech disorders were collected from evaluations by a phoniatric specialist, a speech-language pathologist, or a neuropsychologist. The majority of these patients have some extent of psychomotor delay and global cognitive impairment, but the speech and language deficits are much more severe. All areas of speech and language development are seriously affected; receptive language is less impaired than expressive language, and articulation is the most compromised. For example, at age 8 years, patient 3 had nonverbal cognitive functioning at a 6-year age level, receptive language at a 4.5-year level, expressive language at a 34-mo level, and articulation at a 25-mo level. First words were typically produced at age 3 (mean ± SD 36 ± 14 mo; n=6), whereas most children typically produce their first word (other than "mama" or "dada") by the end of their 1st year. Two patients (3 and 4) started combining words (which typically begins at ∼19 mo) at ages 4 and 6 years, respectively, with the remainder having failed to attain this expressive language milestone. All patients have greatly limited oral vocabulary size. Because of the severe verbal dyspraxia, speech is restricted to the simplest of sounds and is often unintelligible. In their early years, these patients suffered from difficulties with chewing, gagging, and swallowing, often to the extent that aspiration occurred (table 1). Problems with coughing, throat clearing, and sneezing are observed in most patients, and some are unable to blow their noses. Oromotor problems include difficulties with lip protrusion, tongue elevation and lateralization, and rapid alternating movements. In addition to the six patients with DVD with deletion or translocation rearrangements described above, we document another five patients (group F) who all carry de novo deletions of the paternally inherited chromosome that includes the FOXP2 region (table 1 and fig. 1). These individuals could not be given formal diagnoses of DVD since (i) we had limited clinical information about them (e.g., patients 19 and 20) or (ii) they suffered from global developmental delay (e.g., patients 18, 21, and 22) complicating phenotypic assessment. The more complex phenotype in patients 18, 21, and 22 may be due to the larger deletions (all >20 Mb in size) they harbor, compared with the smaller deletions (all <15 Mb in size) observed in the five individuals having confirmed DVD (group A) (table 1). Notwithstanding, we do know that all five group F patients have severe dyspraxia and language delay, with three patients (18, 21, and 22) remaining nonverbal at ages 10, 11, and 20, respectively. In the patients with FOXP2 deletion, there are additional phenotypic complexities, and, although these complexities could be due to the size of the chromosomal lesion (see fig. 1 and table 1), no obvious features are consistently observed. For example, patient 3, who has the smallest deletion (11.3 Mb), meets the full criteria for autism spectrum disorder (ASD [MIM 209850]), on the basis of the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R) exams. Patient 18 was also given a diagnosis of ASD on the basis of similar criteria. Patient 4 (with a 15.4-Mb deletion) was initially given a diagnosis of ASD because she exhibited repetitive behaviors, such as hand flapping, and unusual sensory interests indicated by sniffing and squeezing. On reexamination, however, it was determined that she does not meet full ADOS or ADI-R criteria for ASD because of her strong social communication, which included spontaneous use of varied gestures to compensate for her language difficulties.11Zeesman S Nowaczyk MJ Teshima I Roberts W Cardy JO Brian J Senman L Feuk L Osborne LR Scherer SW Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2.Am J Med Genet A. 2006; 140: 509-514Crossref PubMed Scopus (98) Google Scholar There is a history of Williams-Beuren syndrome (WBS [MIM 194050]) in her family, and she carries the WBS-susceptibility inversion20Osborne LR Li M Pober B Chitayat D Bodurtha J Mandel A Costa T Grebe T Cox S Tsui LC Scherer SW A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome.Nat Genet. 2001; 29: 321-325Crossref PubMed Scopus (245) Google Scholar; because of these complexities, we categorized her as "ASD-like." Patients 1 and 5, who have deletions encompassing the region absent from patient 3, do not exhibit ASD. Importantly, other than DVD, none of the patients with the FOXP2 deletion exhibit any other features commonly observed in patients with SRS. The patients with matUPD7 and SRS (patients 7–13) all have marked speech delay and difficulties in speech output, especially articulation. It is noteworthy that SRS is clinically and genetically heterogeneous, but mainly only patients with complete matUPD7 (∼10% of patients with SRS) exhibit DVD. The dyspraxia phenotype is very similar to that in individuals with FOXP2 deletions but is somewhat milder. First words were usually spoken at 1.5–2.5 years (mean ± SD 24 ± 5.9 mo; n=4). Whereas receptive language skills range from mildly delayed to average, all suffer from impairment in the expressive domain. Articulation difficulties with oromotor dyspraxia make the speech unclear and difficult to understand. This is combined with a limited vocabulary and problems with word finding. Although significant improvement is made over time with targeted speech therapy, the oldest patient (patient 7, age 24 years) is still slightly inarticulate and continues to have problems finding words. Similar to the patients with deletion of FOXP2, the patients with matUPD7 suffered from difficulties with chewing, swallowing, and feeding in the early years. Problems with laughing are observed in most patients, and some have difficulty coughing, sneezing, clearing their throats, and blowing their noses. Although all aspects of oromotor functioning are similar between patients with deletions and patients with matUPD7 in the first year of life, the phenotype in the patients with matUPD7 is milder, and its progression fares better. We note that patient 13 was first referred to the study on the basis of a DVD and ASD diagnosis; the SRS phenotype was assessed only after genotyping revealed matUPD7. To assess how expression of FOXP2 was affected in the different patient groups, we performed quantitative real-time PCR (qPCR), on RNA obtained from lymphoblast cell lines, for a subset of patients (fig. 2). For the deletion group, we included patients 1–4, 18, and 21. The PCR was designed to amplify the forkhead-domain region of FOXP2 (exons 13–14), and GAPDH was used as internal control. Each sample was run in triplicate. The lowest expression was found in the patients with matUPD7, followed by the patients with deletions, the patient with the translocation, the controls, and the patients with patUPD7. The difference in expression among the groups was significant, as assessed by one-way ANOVA (P=.0003), and the post hoc test showed significant difference between patients with matUPD7 and controls and between patients with deletions and controls. There
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