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ABSTRACT: We present the cognitive abilities of females from five families who carry a mutation in a gene (KDM5C, formerly JARIDIC or SMCX) in Xp 11.2 that encodes a transcriptional regulator with histone demethylase activity that is specific for dimethylated and trimethylated H3K4. In this report, the cognitive abilities of females who carry KDMSC mutations are compared to females who carry mutations in other genes known to cause X-linked intellectual and developmental disability (XLIDD) conditions. The KDM5C mutation carriers had higher mean scores on the abstract/visual and quantitative sections of the Stanford-Binet Intelligence Scale: Fourth Edition and lower mean short term memory scores. Implications for counseling are presented.
Genetic counseling (Geneva, Switzerland) 01/2012; 23(1):31-40. · 0.50 Impact Factor
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Clinical Genetics 02/2008; 73(1):94-6. · 3.13 Impact Factor
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ABSTRACT: Golabi, Ito, and Hall reported a family with X linked mental retardation (XLMR), microcephaly, postnatal growth deficiency, and other anomalies, including atrial septal defect, in 1984.
This family was restudied as part of our ongoing study of XLMR, but significant linkage to X chromosome markers could not be found. Extreme short stature and microcephaly as well as other new clinical findings were observed. Mutations in the polyglutamine tract binding protein 1 gene (PQBP1) have recently been reported in four XLMR disorders (Renpenning, Hamel cerebro-palato-cardiac, Sutherland-Haan, and Porteous syndromes) as well as in several other families. The clinical similarity of our family to these patients with mutations in PQBP1, particularly the presence of microcephaly, short stature, and atrial septal defect, prompted examination of this gene.
A missense mutation in PQBP1 was identified which changed the conserved tyrosine residue in the WW domain at position 65 to a cysteine (p.Y65C).
This is the first missense mutation identified in PQBP1 and the first mutation in the WW domain of the gene. The WW domain has been shown to play an important role in the regulation of transcription by interacting with the PPxY motif found in transcription factors. The p.Y65C mutation may affect the proper functioning of the PQBP1 protein as a transcriptional co-activator.
Journal of Medical Genetics 07/2006; 43(6):e30. · 6.36 Impact Factor
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ABSTRACT: We have studied a male patient with significant developmental delay, growth failure, hypotonia, girdle weakness, microcephaly, and multiple congenital anomalies including atrial (ASD) and ventricular (VSD) septal defects. Detailed cytogenetic and molecular analyses revealed three de novo X chromosome aberrations and a karyotype 46,Y,der(X)inv(X) (p11.4q11.2)inv(X)(q11.2q21.32 approximately q22.2)del(X)(q22.3q22.3) was determined. The three X chromosome aberrations in the patient include: a pericentric inversion (inv 1) that disrupted the Duchenne muscular dystrophy (DMD) gene, dystrophin, at Xp11.4; an Xq11.2q21.32 approximately q22.2 paracentric inversion (inv 2) putatively affecting no genes; and an interstitial deletion at Xq22.3 that results in functional nullisomy of several known genes, including a gene previously associated with X-linked nonsyndromic mental retardation, acyl-CoA synthetase long chain family member 4 (ACSL4). These findings suggest that the disruption of DMD and the absence of ACSL4 in the patient are responsible for neuromuscular disease and cognitive impairment.
Cytogenetic and Genome Research 02/2006; 112(1-2):170-5. · 1.53 Impact Factor
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Journal of Medical Genetics 02/2003; 40(1):55-61. · 6.36 Impact Factor
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Journal of Medical Genetics 07/2002; 39(6):430-3. · 6.36 Impact Factor
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ABSTRACT: Coffin-Lowry syndrome (CLS) is an X-linked disorder associated with mental retardation, distinctive facies and hands, hypotonia, and skeletal abnormalities. The syndrome results from mutations in the RSK2 gene located in Xp22.2. Although the syndrome has been elucidated clinically, few, if any, studies have focused on the cognitive deficits of the affected males or carrier females. The subjects of the present study were selected from two African-American families who have the same missense mutation (C340T) in RSK2. The subjects included six affected males, seven carrier females, three normal males and three non-carrier (normal) females. Normal family members served as contrast/comparison cohorts to control for socio-economic, sociocultural and genetic variables which would impinge on intellectual abilities. Analysis of cognitive function, as measured by the Stanford-Binet Intelligence Scale, 4th edn, demonstrated a distinct hierarchy of abilities from normal to carrier to affected patients. The mean composite IQs of the cohorts were 90.8, 65.0 and 43.2 for normal, carrier and affected individuals, respectively. These findings lend support to the clinical concept of negative intellectual effects in carriers of certain X-linked mental retardation conditions. X-inactivation studies showed that carrier females had mild to significant skewing. Normal females in the family did not demonstrate skewing. The correlation coefficient between IQ and X-inactivation status among carriers was not significant.
Clinical Genetics 05/2002; 61(4):299-304. · 3.13 Impact Factor
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ABSTRACT: Three brothers with non-syndromal X-linked mental retardation were found to have a novel missense mutation in FGD1, the gene associated with the Aarskog syndrome. Although the brothers have short stature and small feet, they lack distinct craniofacial, skeletal or genital findings suggestive of Aarskog syndrome. Their mother, the only obligate carrier available for testing, has the FGD1 mutation. The mutation, a C934T base change in exon 4, results in the proline at position 312 to be substituted with a leucine. This missense mutation is predicted to eliminate a beta-turn, creating an extra-long stretch of coiled sequence which may affect the orientations of an SH3 (Src homology 3) binding domain and the first structural conserved region. A new molecular defect associated with non-syndromal X-linked mental retardation affords an opportunity to seek specific diagnosis in males with previously unexplained developmental delays and this opens further predictive tests in families at risk.
Clinical Genetics 03/2002; 61(2):139-45. · 3.13 Impact Factor
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ABSTRACT: X-linked mental retardation (XLMR) was first recognized in the 1940s, long before any human genes had been mapped. It is now estimated that XLMR has a prevalence of 2.6 cases per 1,000 population, accounting for over 10% of all cases of mental retardation. It is likely that over 150 genes are associated with XLMR. Fragile X syndrome, the most common form of XLMR, has a prevalence of about 1 in 4,000 males. Clinically, XLMR exists in syndromic (mental retardation with other somatic, neurological, behavioral, or metabolic findings) and nonsyndromic (mental retardation without other distinguishing features) forms. However, recent findings have caused this distinction to become blurred as mutations in some genes have been found in both syndromic and nonsyndromic XLMR. Progress in XLMR gene identification has allowed some insight into various pathways and cellular activities involved in developing cognitive functions. The genes involve signaling pathways, transcription factors, cytoskeletal organization, cell adhesion and migration, and maintenance of the cell membrane potential.
Cytogenetic and Genome Research 02/2002; 99(1-4):265-75. · 1.53 Impact Factor
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ABSTRACT: Developmental anomalies of the appendicular skeleton are among the most common and easily ascertained birth defects. Split hand/split foot malformations, distinctive in having deficiency of the central rays, occur as isolated anomalies and as one component of multisystem syndromes. The clinical and molecular characterization of a new syndrome, found in two unrelated families, consisting of split foot with hearing loss, is presented here. As in other split hand/split foot conditions, variable expression and reduced penetrance is notable. In the larger family, variably expressed split foot malformations were found in 6 of 11 gene carriers. and mild-to-moderate sensorineural hearing loss in 4. Split hand and cleft lip/palate in one individual and tibial deficiency in another suggest that these malformations are uncommon components of the syndrome. Ectodermal abnormalities did not occur. In the second family, variable split foot was observed in 3 of 4 gene carriers, and sensorineural deafness was present in 3. Split hand was only seen in a gene carrier who also had split foot and deafness. One gene carrier only had deafness. The gene for split hand split foot with sensorineural hearing loss was linked to markers in 7q21 in both families, with a combined (maximum LOD score of 4.37 at theta = 0.0 for locus D7S527) at 80% penetrance. Efforts to identify the responsible gene have not yet been successful.
Clinical Genetics 02/2001; 59(1):28-36. · 3.13 Impact Factor
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ABSTRACT: Follow-up and re-evaluation of four patients originally described as examples of severe infantile "micromelic chondrodysplasia" resembling Kniest disease, "kyphomelic dysplasia," and "Burton skeletal dysplasia" revealed the diagnosis of Schwartz-Jampel syndrome (SJS, myotonic chondrodysplasia) in all of them. SJS may be suspected in neonates with Kniest-like chondrodysplasia, congenital bowing of shortened femora and tibiae, and facial manifestations consisting of a small mouth, micrognathia, and possibly pursed lips. The disorder must be differentiated from the Stüve-Wiedemann syndrome, a genetically distinct myotonic chondrodysplasia with similar clinical but different skeletal changes and an unfavorable early prognosis. The demise of "kyphomelic dysplasia" as a nosological entity reemphasizes the symptomatic nature of congenital bowing of the long bones.
American Journal of Medical Genetics 11/2000; 94(4):287-95.
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American Journal of Medical Genetics 11/2000; 94(5):383-5.
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ABSTRACT: To conduct surveillance for neural tube defects (NTDs) in a high-risk region of the United States and to prevent occurrence and recurrence of NTDs through the periconceptional use of folic acid supplements.
Active and passive methods were used for surveillance of NTD-affected pregnancies and births during a 6-year period (October 1992-September 1998). Individual genetic counseling was used to prevent NTD recurrences and a public awareness campaign was used to reduce NTD occurrences.
State of South Carolina.
All cases of spina bifida, anencephaly, and encephalocele identified among 278 122 live births and fetal deaths to South Carolina residents during 1992-1998 were included.
Changes in occurrence and recurrence rates during a 6-year period.
Over the 6 years of surveillance, the prevalence rates for NTDs decreased from 1.89 to.95 cases per 1000 live births and fetal deaths. The prevalence decrease is explained primarily by a decrease in cases of spina bifida. Isolated NTDs accounted for 297/360 (82%) NTDs and 63/360 (18%) had at least 1 other structural anomaly. Females predominated among isolated NTDs but the sex distribution was equal among NTD cases with other anomalies. Prevalence rates for whites (1.48 cases per 1000 live births and fetal deaths) were higher than rates for blacks (.87 cases per 1000 live births and fetal deaths). There were no NTD recurrences in 113 subsequent pregnancies to mothers of infants with isolated NTDs who took periconceptional folic acid. The rate of periconceptional folic acid use among women of childbearing years increased from 8% to 35% during the 6-year project period.
The prevalence of NTDs in a high-risk region has declined coincident with the increased periconceptional use of folic acid supplements among women of childbearing age.neural tube defects, high-risk region, birth defects, folic acid, spina bifida, anencephaly, encephalocele.
PEDIATRICS 11/2000; 106(4):677-83. · 4.47 Impact Factor
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ABSTRACT: Follow-up and re-evaluation of four patients originally described as examples of severe infantile “micromelic chondrodysplasia” resembling Kniest disease, “kyphomelic dysplasia,” and “Burton skeletal dysplasia” revealed the diagnosis of Schwartz-Jampel syndrome (SJS, myotonic chondrodysplasia) in all of them. SJS may be suspected in neonates with Kniest-like chondrodysplasia, congenital bowing of shortened femora and tibiae, and facial manifestations consisting of a small mouth, micrognathia, and possibly pursed lips. The disorder must be differentiated from the Stüve-Wiedemann syndrome, a genetically distinct myotonic chondrodysplasia with similar clinical but different skeletal changes and an unfavorable early prognosis. The demise of “kyphomelic dysplasia” as a nosological entity reemphasizes the symptomatic nature of congenital bowing of the long bones. Am. J. Med. Genet. 94:287–295, 2000. © 2000 Wiley-Liss, Inc.
American Journal of Medical Genetics 10/2000; 94(4):287 - 295.
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ABSTRACT: A large family is described in which mental retardation segregates as an X linked trait. Six affected males in three generations were studied by linkage and clinical examination.
Characteristic clinical features include short stature, prominent lower lip, small testes, muscle wasting of the lower legs, kyphosis, joint hyperextensibility, abnormal gait, tremor, and decreased fine motor coordination. Affected subjects also had impaired speech and decreased attention span. A carrier female was mildly affected. A similar disorder was not found on review of our XLMR Database of 124 syndromes. Linkage analysis of 37 markers resulted in a lod score of 2.80 at DXS1212 and 2.76 at DXS425. The limiting markers were DXS424 and DXS1047. Ten of 124 XLMR syndromes and eight of 58 MRX families overlap this region.
In summary, this family appears to have a new XLMR syndrome localising to Xq24-q25.
Journal of Medical Genetics 10/2000; 37(9):663-8. · 6.36 Impact Factor
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M J Friez,
F B Essop,
A Krause,
L Castiglia,
A Ragusa,
K Sossey-Alaoui,
R L Nelson,
M M May,
R C Michaelis,
A K Srivastava,
C E Schwartz, R E Stevenson,
A Goldman,
L Villard,
J W Longshore
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ABSTRACT: A recent study suggested that a dodecamer duplication in exon 42 of the HOPA gene in Xq13 may be a significant factor in the etiology of X-linked mental retardation. In an effort to investigate this possibility, we determined the incidence of the dodecamer duplication in cohorts of non-fragile X males with mental retardation from three countries, cohorts of fragile X males from two countries, 43 probands from families with X-linked mental retardation and control cohorts from three countries. The duplication was found in 3.6-4.0% of male patients from two non-fragile X groups (Italy and South Carolina), in 1.2% from another non-fragile X group (South Africa), but in no male patients from families with X-linked mental retardation (South Carolina). The dodecamer duplication was also found in several white males with fragile X syndrome from France (5%) and South Africa (22.2%). Additionally, the duplication was found in 1.5% of South Carolinian newborn males, 2.5% South Carolinian male college students, 5% Italian male controls and 4.5% of the white South African controls. None of the black South African non-fragile X individuals with mental retardation, the fragile X or the control samples tested carried the duplication, suggesting that the duplication is rare in the black South African population. The incidence of the duplication was not significantly different between any of the groups in the study. Therefore, results of our studies in four different populations do not corroborate the findings of the previous study, and indicate that the HOPA dodecamer duplication does not convey an increased susceptibility to mental retardation.
Human Genetics 02/2000; 106(1):36-9. · 5.07 Impact Factor
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M.J. Friez,
F.B. Essop,
A. Krause,
L. Castiglia,
A. Ragusa,
K. Sossey-Alaoui,
R.L. Nelson,
M.M. May,
R.C. Michaelis,
A.K. Srivastava,
C.E. Schwartz, R.E. Stevenson,
A. Goldman,
L. Villard,
J.W. Longshore
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ABSTRACT: A recent study suggested that a dodecamer duplication in exon 42 of the HOPA gene in Xq13 may be a significant factor in the etiology of X-linked mental retardation. In an effort to investigate this possibility, we determined the incidence of the dodecamer duplication in cohorts of non-fragile X males with mental retardation from three countries, cohorts of fragile X males from two countries, 43 probands from families with X-linked mental retardation and control cohorts from three countries. The duplication was found in 3.6-4.0% of male patients from two non-fragile X groups (Italy and South Carolina), in 1.2% from another non-fragile X group (South Africa), but in no male patients from families with X-linked mental retardation (South Carolina). The dodecamer duplication was also found in several white males with fragile X syndrome from France (5%) and South Africa (22.2%). Additionally, the duplication was found in 1.5% of South Carolinian newborn males, 2.5% South Carolinian male college students, 5% Italian male controls and 4.5% of the white South African controls. None of the black South African non-fragile X individuals with mental retardation, the fragile X or the control samples tested carried the duplication, suggesting that the duplication is rare in the black South African population. The incidence of the duplication was not significantly different between any of the groups in the study. Therefore, results of our studies in four different populations do not corroborate the findings of the previous study, and indicate that the HOPA dodecamer duplication does not convey an increased susceptibility to mental retardation.
Human Genetics 12/1999; 106(1):36-39. · 5.07 Impact Factor
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ABSTRACT: To date over 150 X linked mental retardation (XLMR) conditions have been documented. We describe a five generation South African family with XLMR, comprising 16 affected males and 10 carrier females. The clinical features common to the 16 males included profound mental retardation (100%), mutism despite apparently normal hearing (100%), grand mal epilepsy (87.5%), and limited life expectancy (68.8%). Of the four affected males examined, all had mild craniofacial dysmorphology and three were noted to have bilateral ophthalmoplegia and truncal ataxia. Three of 10 obligate female carriers had mild mental retardation. Cerebellar and brain stem atrophy was shown by cranial imaging and postmortem examination. Linkage analysis shows the gene to be located between markers DXS424 (Xq24) and DXS548 (Xq27.3), with a maximum two point lod score of 3.10.
Journal of Medical Genetics 11/1999; 36(10):759-66. · 6.36 Impact Factor
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ABSTRACT: A novel human gene, TRPC5, was cloned from the region of Xq23 that contains loci for nonsyndromic mental retardation (MRX47 and MRX35) and two genes, DCX and HPAK3, implicated in two X-linked disorders (LISX and MRX30). Within a single YAC, we have determined the order cen-HPAK3(5'-3')-DCX(3'-5')-DXS7012E-TRPC5(3'-5' )-ter. TRPC5 encodes a 974-residue novel human protein (111.5 kDa predicted mass) and displays 99% homology with mouse TRP5, (MGD-approved symbol Trrp5) a novel member of a family of receptor-activated Ca2+ channels. It contains eight transmembrane domains, including a putative pore region. A transcript larger than 9.5 kb is observed only in fetal and adult human brain, with a relatively higher level in the adult human cerebellum. We devised an efficient method, Incorporation PCR SSCP (IPS), for detection of gene alterations. Five single-nucleotide variations in the TRPC5 gene were identified in males with mental retardation. However, these were found to be polymorphic variants. Exclusive expression of the TRPC5 gene in developing and adult brain suggests a possible role during development and provides a candidate gene for instances of mental retardation and other developmental defects.
Genomics 10/1999; 60(3):330-40. · 3.02 Impact Factor
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ABSTRACT: The computer database on X-linked mental retardation (XLMR) disorders developed by Arena and Lubs in 1991 has now been updated to include all currently known XLMR disorders and nonspecific (MRX) families. Currently, it includes 123 syndromes, 59 nonspecific XLMR families, and 60 families from the Miami/Greenwood study. The older clinical reports have been reviewed and revised. The search mechanism has also been revised and now includes 740 individual "keywords." Each of these keywords recognizes several of clinical descriptive terms, as used in published literature reports. Searches can be made according to any clinical finding or combination of findings. For each disorder, the database presents a graphic display that contains a revised and more complete set of clinical findings, references, keywords, map localization, molecular information, access to pictures, and OMIM number.
American Journal of Medical Genetics 08/1999; 85(3):202-5.
