Brain Advance Access originally published online on May 21, 2003
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Brain, Vol. 126, No. 7, 1537-1544,
July 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg173
Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia
Departments of 1 Human Genetics, 2 Neuropediatrics and 3 Neuroradiology, Aachen University of Technology, Aachen, Germany
Correspondence to: Carsten Bergmann, MD, Department of Human Genetics, Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany E-mail:cbergmann{at}ukaachen.de
Received July 9, 2002. Revised December 31, 2002. Second revision March 11, 2003. Accepted March 15, 2003.
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Summary |
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We identified an oligophrenin 1 (OPHN1) gene mutation in a family with five brothers affected by a recognizable pattern of clinical and neuroradiological hallmarks. The distinctive phenotype comprised moderate to severe mental retardation, myoclonic-astatic epilepsy, ataxia, strabismus and hypogenitalism. Neuroimaging displayed fronto-temporal atrophy with rostral enlargement of the lateral ventricles, lower vermian agenesis and asymmetric cerebellar hypoplasia. Mutation analysis of the OPHN1 gene on Xq12 disclosed a genomic deletion of exon 19 causing a frameshift. Notably, OPHN1 mutations have been previously reported as a rare cause of non-syndromic X-linked mental retardation. Our findings, however, indicate that OPHN1 mutations result in a recognizable syndrome. In addition, identification of OPHN1 as a further gene associated with epileptic seizures will help to unravel aetiologic factors of epilepsy.
Keywords: X-linked mental retardation; epilepsy; brain anomalies; oligophrenin 1; OPHN1; Rho-GTPase
Abbreviations: OPHN1= oligophrenin 1; PCR = polymerase chain reaction; Rho-GAP = Rho-GTPase activating protein
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Introduction |
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TopSummaryIntroductionSubjects and methodsResultsDiscussionReferences |
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Mental retardation is usually defined as an overall IQ of <70, with an incidence of
3% of the human population (McLaren and Bryson, 1987
; Stevenson et al., 2000). Mental retardation can be roughly classified into syndromic mental retardation and non-syndromic mental retardation. Generally, syndromic mental retardation is clinically recognizable due to a specific pattern of physical, neurological, (neuro)radiological or metabolic features combined with mental retardation. Individuals whose only consistent clinical manifestations are impaired cognitive functions are designated as non-syndromic mental retardation. The disorder has a major genetic component; well-established genetic causes of mental retardation are chromosomal anomalies and several monogenic diseases. X-linked inheritance accounts for the 20–30% excess of males with mental retardation. Knowledge of the monogenic causes of cognitive impairment has increased markedly in recent years and several genes responsible for primary mental retardation or syndromes encompassing mental retardation have been identified (Chelly and Mandel, 2001; Zechner et al., 2001).
The oligophrenin 1 [OPHN1 (MIM 300127)] gene on Xq12 is one of the genes responsible for X-linked mental retardation. OPHN1 has been characterized to encode a Rho-GTPase activating protein (Rho-GAP) involved in the regulation of the G-protein cycle. So far, one causative mutation within the OPHN1 coding sequence has been identified in a single family (Billuart et al., 1998); the authors defined the condition as non-syndromic mental retardation. Involvement of OPHN1 was also suggested in mental retardation patients with gross cytogenetic abnormalities encompassing band Xq12 [translocation t(X;12) in Bienvenu et al., 1997; 1.1 Mb deletion in Tentler et al., 1999]. In addition to mental retardation, these patients all displayed clinical features like epilepsy, fronto-temporally pronounced ventriculomegaly, cerebellar hypoplasia and in part strabismus. However, these additional findings might also have been due to chromosomal imbalance in these patients and thus could not simply be attributed to the OPHN1 alteration. Here, we present a family with an OPHN1 frameshift mutation and a distinct phenotype compatible with those clinical abnormalities observed in previously reported patients with complex cytogenetic alterations of the OPHN1 region (Bienvenu et al., 1997; Tentler et al., 1999). The family described in this report demonstrates that an alteration merely affecting the OPHN1 gene causes a recognizable syndrome comprising mental retardation and epilepsy.
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Subjects and methods |
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Clinical assessment
Five brothers, aged between 2 and 20 years, were affected by moderate to severe mental retardation and generalized epilepsy. EEG recordings were performed by standard procedures. IQ testing was performed using the RAVEN test in the mentally retarded boys, while the Hamburg– Wechsler intelligence test was carried out in the mother and the only girl. All patients have been followed regularly at the Department of Neuropediatrics, Aachen University of Technology, Germany. Blood samples were obtained from the whole family (Fig. 1A) after informed consent had been given. DNA was isolated by standard procedures.
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DNA analysis
Individuals were genotyped for 18 microsatellites covering the X-chromosome on a 10 cM distance. Additional markers were selected to narrow down the candidate interval. The chromosomal order of the markers was taken from the Genethon map (http://www.genethon.fr). Polymerase chain reaction (PCR) amplification of microsatellite sequences was performed with oligonucleotide primers from the Genethon database. PCR products were electrophoresed on a 6% denaturating polyacrylamide gel and bands were visualized by silver staining.
Primer sets for PCR amplification of OPHN1 coding exons 2–24 were as described by Billuart et al. (2000). PCR products were sequenced directly using the Dye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems, Foster City, CA, USA). Samples were run and analysed on an ABI PRISM 377 fluorescent DNA sequencer (Applied Biosystems).
As the OPHN1 nucleotide sequence from exons 11–20 is contained in genomic clone RP11–516A11 (Gene Bank accession AL158201; http://www.ncbi.nlm.nih.gov/Genbank), we chose a PCR-based strategy to search for a putative deletion. In a first step, we amplified several 150–250 bp genomic fragments placed every 3–5 kb within the 38.5 kb sequence of OPHN1 introns 18 and 19. Primers from the fragments found to be situated just outside the deletion were subsequently used to amplify the breakpoint region. The junction fragment was sequenced directly with the PCR primers and with additional internal oligonucleotides. After the exact positions of the breakpoints had been identified, primers were designed for diagnostic detection of the OPHN1 deletion mutation (Fig. 1C). These four primers were used in a single PCR reaction.
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Results |
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Clinical data
Five sons from healthy, non-consanguineous parents of German descent were affected by moderate to severe mental retardation and an infantile-onset epilepsy syndrome. The only daughter displayed mild learning disabilities. Both parents and four further sons neither showed intellectual impairment nor suffered from epilepsy (Table 1 and Fig. 1A). Further family history was unremarkable. Pregnancy, delivery and neonatal period were uneventful in all children. Neonatal head circumference, length and weight as well as postnatal growth charts were within the normal range. All five mentally retarded boys had a history of single myoclonic jerks and absences first noticed as occasional events during the first months of life which, at first, had been interpreted by the parents as startled responses. By the end of the first year of life or shortly thereafter, the boys had been referred to our hospital because of an increasing frequency of seizures, a history of psychomotor retardation, hypotonia and ataxia. Patient II-9, who is the most severely affected amongst the sibship, was referred at the age of 10 months with the diagnosis of malnutrition (weight below the 3rd percentile) and severe hypotonia.
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None of the gene carriers was dysmorphic (Fig. 2A–D). However, all affected patients presented with cryptorchidism, hypoplastic scrotum and microphallus (testicular volume was 6 ml and 3 ml in Patients II-3 and II-6, respectively). Furthermore, puberty was delayed in the three elder affected males. Testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) baseline levels, as well as values after human chorionic gonadotropin (HCG) and luteinizing hormone–releasing hormone (LH–RH) stimulation, were normal. Genital development was normal in the only girl child and in the unaffected boys. Another feature observed in all mentally retarded boys as well as mother and daughter was congenital strabismus (Fig. 2A–D), with reduced visual acuity due to ocular refractive errors which improved after appropriate ophthalmologic treatment. Fundoscopy was normal in all probands.
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All five retarded boys had a history of single myoclonic jerks first noticed during the first months of life; the frequency of these jerks increased by the end of the first year. The epileptic seizures cannot be classified properly according to the International League Against Epilepsy, but most closely mimic the centrencephalic myoclonic-astatic epilepsy described by Doose et al. (1970)
. The seizures manifested as generalized short-lasting (1–2 s) myoclonic jerks and involved the axial and all limb muscle groups occurring at a daily frequency of up to 20 attacks by the end of the first year. Simultaneously, all patients manifested absences that occurred independently of the myoclonic fits as single episodes up to a maximum of 15 s and did not proceed into non-convulsive (petit mal) status. With advancing age (up to the age of 6 years), the frequency of myoclonic fits and absences declined. After the age of 6 years, the spectrum of epileptic seizures changed to generalized tonic–clonic seizures with a maximum annual frequency of three attacks. During brief generalized myoclonic fits, ictal EEG recordings showed generalized outbursts of irregular spike–slow wave complexes of 1–2 Hz with a duration of 1.5–2 s. In the first year, interictal EEG recordings showed long runs of parieto-occipital high-amplitude delta waves with occasional generalized slowing over both hemispheres. Photostimulation could neither provoke clinical convulsions nor elicit EEG discharges. The combination of valproate and lamotrigen appeared to be the most effective anticonvulsive treatment. The EEG recordings normalized during this anticonvulsive regimen. None of the four healthy brothers nor the single sister nor the parents suffered from epilepsy. Motor milestone development was moderately to severely delayed amongst all affected boys. Patients II-9 and II-10 had severe motor delay and were not able to stand without support at the age of 2 and 5 years, respectively. Moderate delay of motor milestone development was also present in the other three retarded boys. They became able to walk independently before the age of 2 years (period ranging from 19 to 24 months). However, gait remained ataxic and the boys would frequently stumble and fall as reported by the parents.
The five affected brothers displayed moderate to severe mental retardation, which has been assessed by utilizing the RAVEN test; the Hamburg–Wechsler intelligence test was carried out with the mother and the only girl. Compulsory education was not possible in any affected boy, but the degree of mental retardation varied. Patients II-2 and II-3 (currently 21 and 20 years old, respectively) possessed rudimentary verbal skills, were able to perform simple tasks and worked at a sheltered place for disabled people. Patient II-2 was able to read and understand simple sentences. Both brothers’ performance in the RAVEN test was below the lower limit (IQ<55) indicating ‘moderate mental retardation’. Patient II-6, who was 13 years old, attended a school for the mentally handicapped. He spoke only single words and lacked the comprehension to perform simple tasks. In keeping with this, the RAVEN test could not be carried out. The two youngest sibs, Patients II-9 and II-10 (5 and 2 years old, respectively), also displayed ‘severe mental retardation’ without development of active or passive speech. It might be speculated that in the most severely affected, Patient II-9, cognitive deficits might have been aggravated by malnourishment in early infancy. The only daughter, proband II-5, who was 15 years old, attended a Montessori school due to poor school achievement at regular school. Using the Hamburg– Wechsler intelligence test, her total performance was 75, with a score on verbal subtests significantly lower than those for performance tasks (70 and 87, respectively). Hamburg– Wechsler intelligence testing performed in the mother revealed an overall IQ of 118.
Further neurological examination of patients II-2, II-3 cdII-6 showed normal consciousness and orientation with intact cranial nerve function, muscular strength and tendon reflexes despite persistence of moderate muscle hypotonia after the toddler age. Upon neurological testing at a later age, gait was still ataxic. Intention tremor was noted on finger–nose pointing. Sensory deficits could not be noted on examination.
Neurophysiological findings
Given delayed motor development with signs of ataxia and hypotonia, neurophysiological testing was performed in affected Patients II-3 and II-9. Results included normal EMG and nerve conduction studies. Serial recordings of flash visual evoked potentials were performed when Patient II-9 was 10 months and 2 years old. At the age of 10 months, N2 waves were absent and P2 waves demonstrated normal latencies with low-amplitude, which became of normal amplitude at the age of 2 years. At the age of 2 years, somatosensory evoked potentials following tibial nerve stimulation did not show a clear response. Auditory evoked potentials after monaural stimulation with an intensity of 70 dB showed normal responses. However, with progressive reduction of the stimulus intensity below 50 dB, all recognizable auditory evoked potentials disappeared. Similar findings for somatosensory and auditory evoked potentials were found in the elder sib, Patient II-3.
Neuroradiological findings
Neuroradiological examination included cranial CTs for all affected sons. Cranial MRI scans were available for affected Patients II-3 and II-9, for both parents and for the only daughter. Neuroimaging showed a frontally and temporally pronounced cerebral volume reduction with a widened interhemispheric fissure (Fig. 3A–E). Cerebral ventricles were widened with the frontal horn of the lateral ventricles most prominently enlarged, while the fourth ventricle appeared normal. Bilateral hypoplasia of the head of the caudate nucleus was present and gave a further balloon-like appearance to the frontal horn. There was lower vermian agenesis and bilateral cerebellar hypoplasia with asymmetric involvement. The neocerebellar cortex showed a localized and broad, ill-shaped cortical architecture lacking the normal folia. Brainstem and medulla appeared of normal size and shape. Comparison of the scans at different ages showed no progression of the abnormalities. The parents and the sister had normal MRI scans.
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Laboratory parameters
Normal results in all affected sibs were obtained for routine laboratory parameters, lactate, pyruvate, ammonia, phytanic acid and very long chain fatty acids as well as urinary amino acid and organic acid chromatography. Furthermore, CSF glucose, protein and cell count were in the normal range. High-resolution chromosome analysis and molecular genetic screening for fragile-X syndrome were non-contributory.
Haplotype analysis and OPHN1 mutation analysis
Linkage data confirmed X-linked inheritance in our family and suggested assignment of the disease locus between DXS988 and DXS990 (Fig. 1A). These microsatellites flank an interval of 18.3 cM on the sex-averaged Genethon map in chromosomal region Xp11.21–Xq21.33. The locus for OPHN1, which was reported as a candidate gene for mental retardation, has previously been mapped to Xq12 (Billuart et al., 1998). PCR amplification of OPHN1 exon 19 failed in DNA samples from our patients but was obtained in healthy sibs, the only girl child, the mother and the father. Amplification of sequences corresponding to exons 18 and 20 was possible in all family members. These findings pointed at a genomic deletion with putative breakpoints in introns 18 and 19. Direct sequencing of the OPHN1 coding exons 2–24 did not unravel any alterations.
Characterization of the deletion mutation
The precise extent of this deletion was defined using amplification of short sequences spread over this genomic region. Fragments placed 4.9 kb upstream of exon 19 and 15.7 kb downstream of exon 19 were found to lie just outside the deletion (i.e. these fragments yielded amplification in patients’ DNA while fragments situated between these markers gave no products). Primers from the identified flanking segments were combined to amplify the putative breakpoint region. These oligonucleotides bracketed a segment of 20.6 kb on the reference allele represented by clone RP11-516A11. As expected, no product was obtained when using DNA of healthy family members under standard PCR conditions. However, amplification of patient DNA yielded a fragment of 3.0 kb, suggesting a deletion of 17.6 kb of genomic DNA. Sequencing of the junction fragment allowed precise identification of the deletion breakpoints (Fig. 1B). PCR with primers flanking the breakpoints produced 455 bp and 517 bp PCR products in case of a normal sequence in healthy family members including the mother and the daughter. In case of the deletion, PCR resulted in a 402 bp product as shown in the affected boys, the mother and the daughter (Fig. 1C).
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Discussion |
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We established molecular diagnosis in a family where five boys were affected by a syndrome comprising mental retardation and epilepsy as well as hypogenitalism, strabismus and distinctive neuroradiologic findings. The pedigree pattern was compatible with an X-chromosomal as well as an autosomal recessive mode of inheritance. However, lack of parental consanguinity and presence of a limited phenotype in females (strabismus in the mother, strabismus and learning deficits in the only daughter) justified analysis of the X-chromosome as the initial step to disclose the causative gene defect. Haplotype analysis made it very likely that the phenotype in our family is linked to Xp11.21–Xq21.33 encompassing an interval of 18.3 cM on the Genethon genetic map. Hitherto, five genes for X-linked mental retardation have been mapped within this interval; however, no epilepsy gene has been assigned to this locus. Genes responsible for Aarskog syndrome (MIM 305400), ATR-X syndrome (MIM 301040), Menkes disease (MIM 309400) and PGK1 deficiency (MIM 311800) were initially regarded as unlikely as no compatible phenotype was present. The remaining known gene, OPHN1, was subjected to mutation analysis, although it has been proposed to be involved in patients with unspecific mental retardation. Affected patients from our family were found to carry a deletion of exon 19 that disrupted the OPHN1 open reading frame. A gross deletion in Xp11.21–Xq21.33 could be excluded by high resolution chromosome analysis.
So far, mutations of OPHN1 have been attributed to cause non-syndromic mental retardation. However, patients from our family display distinctive phenotypic features. In keeping with this, patients bearing gross cytogenetic deletions or translocations involving the OPHN1 locus showed a similar pattern of additional clinical signs (Bienvenu et al., 1997; Tentler et al., 1999). In these cases, however, additional features could not be simply attributed to the OPHN1 genotype as other contiguous genes or positional effects might have contributed to the displayed phenotype. Therefore, our family allows for the first time the delineation of a recognizable syndrome originating from a mutation solely affecting the OPHN1 gene.
The del ex19 mutation is known to cause a frameshift leading to premature stop of translation after incorporation of three OPHN1 unrelated amino acids interrupting the functionally relevant Rho-GAP domain (Billuart et al., 1998). Alternatively, expression of the mutant allele might fail on the transcriptional or translational level. Conclusively, OPHN1 del ex19 most likely represents a null-allele resulting in loss of OPHN1 function.
The deletion in this family comprises 17.6 kb of the OPHN1 gene ranging from intron 18 to intron 19. Analysis of the sequences spanning the deletion breakpoints performed by the RepeatMasker Documentation program (http://repeatmasker.genome.washington.edu) suggested that the deletion mechanism is Alu-mediated (Fig. 3D). Specifically, a recombination event between two highly homologous AluY repeats within introns 18 and 19 is likely to be responsible for the occurrence of the deletion, and the site of the crossover event lies within a 6 bp sequence (GCGGAG). Moreover, introns 18 and 19 contain various additional repetitive sequences including Alu and other interspersed repetitive elements as well as simple repeats. The human genome contains 1 x 106 copies of Alu repeats distributed throughout the genome with an average spacing of 4 kb. These sequences are known to be hotspots for rearrangements of genomic DNA, which have been shown to cause a number of inherited diseases (Lehrman et al., 1987; Stoppa-Lyonnet et al., 1990; Morgan et al., 1999). It might be noteworthy that the 3'-Alu breakpoint sequence is bracketed by a Tigger1-element representing an ancient transposon fossile (Smit and Riggs, 1996). Accordingly, the OPHN1 locus may be particularly susceptible to DNA rearrangements.
As well as OPHN1, there are two further genes known for X-linked mental retardation [ARHGEF6 (MIM 300267), PAK3 (MIM 300142)] that encode proteins involved in the Rho-GTPase cycle (Allen et al., 1998; Kutsche et al., 2000). These Rho proteins are ubiquitously expressed with high levels in developing neuroepithelium. They are likely to function as mediators linking the extracellular growth and guiding signals induced by cell-surface adhesion molecules to the intracellular signal transduction pathways that are important for neuronal morphogenesis as well as for cytoskeletal dynamics of elongation and orientation of the actin molecules of the cytoskeleton within neuronal growth cones (Schmitz et al., 2000; Brouns et al., 2001). It might be speculated that disturbance of such pathways influencing growth and guidance of axon outgrowth at neuronal growth cones might lead to impaired formation of brain structures due to, for example, disguided and delayed axonal outgrowth. In the context of our neurophysiological investigations amongst two affected patients, this merits particular attention as the abnormal findings of visual, somatosensory and auditory evoked potentials being of low amplitude or showing no response at an early age might hint at disguided axonal outsprouting due to loss of OPHN1 function. Indirect evidence about the effect of loss of function of Rho-GAP can be found in studies on genetically modified mice (Brouns et al, 2001), but still remains speculative among affected humans with OPHN1 genetic defects.
It has been demonstrated that mutations of another protein involved in G-protein cycle regulation, GDI1. (MIM 300104), cause X-linked mental retardation associated with epileptic seizures (Ishizaki et al., 2000). More recently, a homeobox gene [ARX (MIM 300382)] was identified to result in X-linked mental retardation with generalized epilepsy (Stromme et al., 2002). Epilepsy is a consistent feature of the clinical picture in our patients and manifested as myoclonic seizures associated with absences and tonic-clonic seizures. Over 100 Mendelian disorders include epilepsy as one component (Gardiner, 1999), while the majority of idiopathic epilepsies display a multifactorial pattern of inheritance. While significant advances have been made in the understanding of the genetic basis of some hereditary epilepsies, the nosology of seizures remains undetermined in most patients. Therefore, identification of OPHN1 as a further gene causing epilepsy will contribute to the unravelling of the aetiology of epilepsy.
Furthermore, all affected boys consistently show a micropenis and small testes without any hormonal imbalance. Hypogenitalism is associated with mental retardation in different autosomal syndromes such as Prader–Willi syndrome (MIM 176270), Bardet–Biedl syndrome (MIM 209900) and the rare Biemond syndrome (MIM 210350) (Verloes et al., 1997). It is also described as a feature in X-linked mental retardation syndromes, e.g. in MEHMO [MR, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, obesity (MIM 300148)], which has been assigned to Xp21.1–Xp22.13 (Steinmuller et al., 1998), and in other syndromes (Seemanova et al., 1996) whose genetic basis is still unknown. Also, neuronal migration defects can be associated with hypogenitalism (Pradhan et al., 1999). The pathogenetic pathway of hypogenitalism in these syndromes is not well understood, but is believed to be of hypothalamic origin at least in Prader–Willi syndrome, where low gonadotropin levels can be measured in some but not all patients. In most patients with Bardet–Biedl syndrome, hypogonadotropism has been excluded as a reason for the observed small testes and genitalia (Green et al., 1989). Since there was no hormonal dysfunction in our patients, an endocrine cause of the hypogenitalism seems to be excluded. While Rho proteins have not been reported to be involved in genital development, it would be interesting to study those factors that cause hypogenitalism along with mental deficiency.
Female carriers seem to be clinically hardly detectable since strabismus represented the only consistent clinical feature in the mother and the daughter. While the mother showed normal intelligence, the only daughter exhibited moderate deficits especially of verbal skills. However, this phenomenon can easily be attributed to skewed X-inactivation as already described in various X-linked disorders including X-linked mental retardation (Willard, 1996; Amir and Zoghbi, 2000; Shastry, 2000).
In conclusion, our findings suggest that OPHN1 gene alterations resulting in loss of function cause a recognizable syndrome of moderate to severe X-linked mental retardation, myoclonic-astatic epilepsy, ataxia, strabismus, hypogenitalism and specific brain anomalies which include fronto-temporal atrophy with rostral enlargement of the lateral ventricles, lower vermian agenesis and asymmetric cerebellar hypoplasia. A large study of 164 patients with non-syndromic mental retardation suggests that OPHN1 mutations are rarely involved in mentally retarded without additional clinical features (Billuart et al., 2000). In contrast, mutation analysis of OPHN1 seems to be advisable in case of X-linked mental retardation combined with a recognizable pattern of abnormalities such as in our family.
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Acknowledgements |
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The authors wish to thank the family of the present study for their participation and co-operation.
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References |
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