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1.  Clinical studies on submicroscopic subtelomeric rearrangements: a checklist 
Journal of Medical Genetics  2001;38(3):145-150.
BACKGROUND—Submicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions.
METHODS—We studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history. Controls were 110 children with mental retardation of unknown aetiology with normal G banded karyotype and no detectable submicroscopic subtelomeric abnormalities.
RESULTS—Prenatal onset of growth retardation was found in 37% compared to 9% of the controls (p<0.0005). A higher percentage of positive family history for mental retardation was reported in the study group than the controls (50% v 21%, p=0.002). Miscarriage(s) were observed in only 8% of the mothers of subtelomeric cases compared to 30% of controls (p=0.028) which was, however, not significant after a Bonferroni correction. Common features (>30%) among subtelomeric deletion cases were microcephaly, short stature, hypertelorism, nasal and ear anomalies, hand anomalies, and cryptorchidism. Two or more facial dysmorphic features were observed in 83% of the subtelomere patients. None of these features was significantly different from the controls. Using the results, a five item checklist was developed which allowed exclusion from further testing in 20% of the mentally retarded children (95% CI 13-28%) in our study without missing any subtelomere cases. As our control group was selected for the "chromosomal phenotype", the specificity of the checklist is likely to be higher in an unselected group of mentally retarded subjects.
CONCLUSIONS—Our results suggest that good indicators for subtelomeric defects are prenatal onset of growth retardation and a positive family history for mental retardation. These clinical criteria, in addition to features suggestive of a chromosomal phenotype, resulted in the development of a five item checklist which will improve the diagnostic pick up rate of subtelomeric defects among mentally retarded subjects.

Keywords: submicroscopic subtelomeric rearrangements; clinical preselection; checklist; chromosome deletion.
PMCID: PMC1734836  PMID: 11238680
2.  The use of array-CGH in a cohort of Greek children with developmental delay 
The genetic diagnosis of mental retardation (MR) is difficult to establish and at present many cases remain undiagnosed and unexplained. Standard karyotyping has been used as one of the routine techniques for the last decades. The implementation of Array Comparative Genomic Hybridization (array-CGH) has enabled the analysis of copy number variants (CNVs) with high resolution. Major cohort studies attribute 11% of patients with unexplained mental retardation to clinically significant CNVs. Here we report the use of array-CGH for the first time in a Greek cohort. A total of 82 children of Greek origin with mean age 4.9 years were analysed in the present study. Patients with visible cytogenetic abnormalities ascertained by standard karyotyping as well as those with subtelomeric abnormalities determined by Multiplex Ligation-dependent Probe Amplification (MLPA) or subtelomeric FISH had been excluded.
Fourteen CNVs were detected in the studied patients. In nine patients (11%) the chromosomal aberrations were inherited from one of the parents. One patients showed two duplications, a 550 kb duplication in 3p14.1 inherited from the father and a ~1.1 Mb duplication in (22)(q13.1q13.2) inherited from the mother. Although both parents were phenotypically normal, it cannot be excluded that the dual duplication is causative for the patient's clinical profile including dysmorphic features and severe developmental delay. Furthermore, three de novo clinically significant CNVs were detected (3.7%). There was a ~6 Mb triplication of 18q21.1 in a girl 5 years of age with moderate MR and mild dysmorphic features and a ~4.8 Mb duplication at (10)(q11.1q11.21) in a 2 years old boy with severe MR, multiple congenital anomalies, severe central hypotonia, and ataxia. Finally, in a 3 year-old girl with microcephaly and severe hypotonia a deletion in (2)(q31.2q31.3) of about ~3.9 Mb was discovered. All CNVs were confirmed by Fluorescence in situ hybridization (FISH). For the remaining 9 patients the detected CNVs (inherited duplications or deletions of 80 kb to 800 kb in size) were probably not associated with the clinical findings.
Genomic microarrays have within the recent years proven to be a highly useful tool in the investigation of unexplained MR. The cohorts reported so far agree on an around 11% diagnostic yield of clinically significant CNVs in patients with unexplained MR. Various publicly available databases have been created for the interpretation of identified CNVs and parents are analyzed in case a rare CNV is identified in the child. We have conducted a study of Greek patients with unexplained MR and confirmed the high diagnostic value of the previous studies. It is important that the technique becomes available also in less developed countries when the cost of consumables will be reduced.
PMCID: PMC2987877  PMID: 21062444
3.  Accuracy of the clinical diagnosis of Down syndrome. 
The Ulster Medical Journal  2004;73(1):4-12.
OBJECTIVES: To determine the accuracy of clinical diagnosis of Down syndrome, identify problems in reaching a diagnosis, to provide recommendations for improvement and estimate a minimum prevalence for all types of Down syndrome. DESIGN: A retrospective observational study was carried out over a five-year period. Genesis, a database located in the Department of Medical genetics, was used to identify the number of Down syndrome karyotypes including trisomy, translocation, and mosaic sample variants. Age of diagnosis was determined using date of receipt. Karyotyping requests for a clinical diagnosis of Down syndrome were also identified. Patient notes and cytogenetic laboratory reports were used to identify clinical indication for karyotyping. SETTING: Regional Genetics Centre, covering all cytogenetic analyses for referrals within the entire Northern Ireland population. RESULTS: 208 postnatal cases of Down syndrome were identified, 197 (94.7%) trisomy, 3 (1.45%) translocation, and 8 (3.85%) mosaic variants. 112 (54.8%) were male and 96 (46.2%) female. 268 samples were taken to confirm or exclude a clinical diagnosis of Down syndrome. 185 of these had Down syndrome, 77 were normal, and 6 had another abnormality. 90% and 100% of trisomy and translocation Down syndrome respectively were diagnosed on the basis of clinical features. This fell to 37.5% of mosaic Down syndrome patients being diagnosed clinically (p < 0.001). Simian crease, sandal gap, epicanthic folds, hypotonia, upslanting palpebral fissures, and protruding tongue are the most frequent characteristic features seen. Similarly epicanthic folds, protruding tongue, simian crease and sandal gap, hypotonia, and upslanting palpebral fissures are also described in a significant proportion of karyotypically normal individuals, thus arousing a suspicion of Down syndrome. 89.4% of patients were diagnosed between day 1 and 7 of life. Of 10.6% patients diagnosed after day 7 of life, 7.6% were adults and 3% children. The minimum prevalence was estimated at 167.9 per 100,000, or 1 in 595 births. CONCLUSION: In a defined population, with a prevalence of around 1 in 600 births, accurate clinical diagnosis occurred in 90%, 100%, and 37.5% of trisomy, translocation, and mosaic patients. 49.5% of patients had one or more of the following phenotypic findings: Simian crease, sandal gap, epicanthic folds, hypotonia, upslanting palpebral fissures, and protruding tongue. However, the same six features aroused a suspicion of Down syndrome in individuals with normal karyotyping, thus causing undue stress and worry to parents. Mosaic cases may be more common than previously recognised, and often do not have dysmorphic features. It is therefore a diagnosis that should always be considered in those who are educationally subnormal without a definitive diagnosis.
PMCID: PMC2475449  PMID: 15244118
4.  High resolution comparative genomic hybridisation in clinical cytogenetics 
Journal of Medical Genetics  2001;38(11):740-744.
High resolution comparative genomic hybridisation (HR-CGH) is a diagnostic tool in our clinical cytogenetics laboratory. The present survey reports the results of 253 clinical cases in which 47 abnormalities were detected. Among 144 dysmorphic and mentally retarded subjects with a normal conventional karyotype, 15 (10%) had small deletions or duplications, of which 11 were interstitial. In addition, a case of mosaic trisomy 9 was detected. Among 25 dysmorphic and mentally retarded subjects carrying apparently balanced de novo translocations, four had deletions at translocation breakpoints and two had deletions elsewhere in the genome. Seventeen of 19 complex rearrangements were clarified by HR-CGH. A small supernumerary marker chromosome occurring with low frequency and the breakpoint of a mosaic r(18) case could not be clarified. Three of 19 other abnormalities could not be confirmed by HR-CGH. One was a Williams syndrome deletion and two were DiGeorge syndrome deletions, which were apparently below the resolution of HR-CGH. However, we were able to confirm Angelman and Prader-Willi syndrome deletions, which are about 3-5 Mb. We conclude that HR-CGH should be used for the evaluation of (1) dysmorphic and mentally retarded subjects where normal karyotyping has failed to show abnormalities, (2) dysmorphic and mentally retarded subjects carrying apparently balanced de novo translocations, (3) apparently balanced de novo translocations detected prenatally, and (4) for clarification of complex structural rearrangements.

Keywords: comparative genomic hybridisation; chromosome analysis; chromosome aberrations; dysmorphism
PMCID: PMC1734756  PMID: 11694545
5.  Two cases of partial trisomy 8p and partial monosomy 21q in a family with a reciprocal translocation (8;21)(p21.1;q22.3). 
Journal of Medical Genetics  1998;35(7):604-608.
We report on two mentally retarded adults with an unbalanced karyotype resulting from a familial balanced translocation between chromosomes 8 and 21, t(8;21)(p21.1;q22.3). This translocation has not been reported before. Both patients had partial trisomy 8p and partial monosomy 21q. Fluorescence in situ hybridisation (FISH) was used to determine the chromosomal breakpoints more precisely. The first patient showed mild mental retardation and facial dysmorphism, slightly resembling the earlier described trisomy 8p phenotype. He did not resemble his affected niece, who was more severely retarded, had serious epilepsy, but lacked the facial dysmorphism. Comparing the data of both patients with published reports of trisomy 8p, marked differences were found between patients with an inversion duplication (inv dup) 8p, patients with partial trisomy 8p caused by an unbalanced translocation, and our patients. Inv dup(8p) causes a recognisable phenotype, whereas the phenotype of trisomy 8p resulting from a translocation is much more variable, probably because of the accompanying monosomies. However, even the same abnormal karyotype can cause different phenotypes, as our patients show. Counselling carriers of the balanced translocation in this family, a 20-25% recurrence risk for unbalanced offspring and a 25% risk for miscarriages seem appropriate.
PMCID: PMC1051374  PMID: 9678708
6.  Tremor in 48,XXYY Syndrome 
The 48,XXYY syndrome is a form of sex chromosome aneuploidy presenting in 1:18,000 males. Tremor has been previously reported in 47,XXY and 47,XYY syndromes, but has not been well described in 48,XXYY syndrome. Ten males with 48,XXYY syndrome had a standardized neurological examination and videotaping, which included the Clinical Rating Scale for Tremor and the International Cooperative Ataxia Rating Scale. All 10 cases had postural and kinetic tremor on physical examination. Other findings included mild gait ataxia, dysarthria, and nystagmus. Three cases are reviewed. Tremor is a common finding in children and young adults with 48,XXYY syndrome. Dosage alteration of genes on the sex chromosomes may be involved in the pathogenesis of this tremor. Karyotyping should be considered in individuals presenting with tremor and a history of developmental delay, learning disabilities, tall stature, or micro-orchidism.
PMCID: PMC3056502  PMID: 19705466
XXYY syndrome; sex chromosome abnormality; XYY; XXY; Klinefelter syndrome; tremor
7.  A Case with Mega Cisterna Magna Renal and Ear Anomalies: Is This a New Syndrome? 
Case Reports in Medicine  2013;2013:149656.
Background. Extrarenal pathologies may be associated with renal position and fusion anomalies. According to the literature, our patient is the first horseshoe kidney case that had mega cisterna magna, arachnodactyly, and mild mental retardation. Case Report. A 9-year-old boy admitted because of the myoclonic jerks. He had a dysmorphic face, low-set and cup-shaped ears, arachnodactyly, and mild mental retardation. The patient's laboratory findings were normal except for a mild leucocytosis and hypochromic microcytic anemia. His cerebrospinal fluid was cytologically and biochemically normal. Cranial MRI revealed 1.5 cm diametered mega cisterna magna in the retrocerebellar region. Although there were no significant epileptical discharges in the electroencephalography, there were slow wave discharges arising from the anterior regions of both hemispheres. Because he had stomachache, abdominal ultrasonography was performed, and horseshoe kidney was determined. Abdominal CT did not reveal any abnormalities except the horseshoe kidney. There were not any cardiac pathologies in echocardiography. He had normal 46XY karyotype and there were no repeated chromosomal derangements, but we could not evaluate for molecular and submicroscopic somatic changes. He was treated with valproic acid and myoclonic jerks did not repeat. Conclusion. We suggest that the presence of these novel findings may represent a newly recognized, separate syndrome.
PMCID: PMC3671267  PMID: 23762068
8.  The recurrence risks for mild idiopathic mental retardation. 
Journal of Medical Genetics  1989;26(4):260-266.
A genetic study of children attending ESN(M) schools in Coventry has shown a recurrence risk of idiopathic mental retardation in sibs lying between 1 in 4 and 1 in 5. There was also a prevalence of mental retardation in other relatives that was greater than the population prevalence, and was less for second degree relatives than for first degree, and less still for third degree relatives. Recurrence in sibs was greater if more than one first degree relative was affected. There was no suggestion of a contribution by X linked genes, once the fragile X syndrome had been excluded. The presence of perinatal and other environmental factors in the index children did not alter the recurrence risk for sibs except for very low birth weight. There was a low recurrence rate of mental retardation in Asian families, suggesting that they had a different distribution of intelligence from non-Asian families.
PMCID: PMC1017300  PMID: 2785601
9.  48XXYY Syndrome in an Adult with Type 2 Diabetes Mellitus, Unilateral Renal Aplasia, and Pigmentary Retinitis 
Case Reports in Medicine  2010;2010:612315.
A 45-year-old male was referred for diabetes mellitus. Clinical examination found a family history of multiple precocious deaths, strong consanguinity, personal history of seizures during childhood, small testicles, small penis, sparse body hair, long arms and legs, dysmorphic features, mental retardation, dysarthria, tremor, and mild gait ataxia. Investigations found pigmentary retinitis, metabolic syndrome, unilateral renal aplasia, and hypergonadotropic hypogonadism, and ruled out mitochondrial cytopathy and leucodystrophy. Karyotype study showed a 48XXYY chromosomal type. Renal aplasia and pigmentary retinitis have not been described in 48XXYY patients. They may be related to the chromosomal sex aneuploidy, or caused by other genetic aberrations in light of the high consanguinity rate in the patient's family.
PMCID: PMC2934777  PMID: 20827436
10.  Partial and complete trisomy 14 mosaicism: clinical follow-up, cytogenetic and molecular analysis 
Molecular Cytogenetics  2014;7(1):65.
Trisomy 14 mosaicism is a rare chromosomal abnormality. It is associated with multiple congenital anomalies. We report a 15 year-old female with an unusual karyotype with three cell lines: 47,XX,+mar/47,XX,+14/46,XX. At six months old she had short stature, cleft palate, hyperpigmented linear spots in arms and legs and developmental delay. At present, she has mild facial dysmorphism and moderate mental retardation.
Cytogenetic analysis was performed in peripheral blood lymphocytes and in the light and dark skin following standard methods. DNAarray – Oligo 180 k was carried out using Agilent Technologies and FISH analysis was accomplished using DNA BACs probes to confirm the result obtained by DNAarray. Methylation-Specific PCR (MS-PCR) of the MEG3 promoter and microsatellite analysis were performed.
Microarray analysis confirmed partial trisomy 14 mosaicism; the marker chromosome was found to be from chromosome 14, the result was confirmed with FISH. Methylation (14q32.3) and microsatellite (14q11-14q32.33) analysis were carried out and UPD was discarded. The global result was: mos 47,XX,+del(14)(q11.2)[45]/47,XX,+14[10]/46,XX[45].
This is a unique case because of the coexistence of two abnormal cell lines, including one with +14 and another with +del(14)(q11.2). To our knowledge, only three patients have been reported with trisomy 14 and another abnormal cell line. The array analysis identified the marker chromosome and characterized the breakpoint. The del(14)(q11.2) does not seem to be related to any particular phenotypic characteristic of the patient; the clinical features of our patient observed until now, can be attributed to trisomy 14 mosaicism. Nevertheless, we cannot discard the manifestation of new symptoms related to her karyotype in the future.
Electronic supplementary material
The online version of this article (doi:10.1186/s13039-014-0065-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4180134  PMID: 25276227
Marker chromosome 14; Trisomy 14 mosaicism; Deletion 14q11.2; Microarray analysis
11.  Identification of Chromosome Abnormalities in Subtelomeric Regions by Microarray Analysis: A Study of 5,380 Cases 
Subtelomeric imbalances are a significant cause of congenital disorders. Screening for these abnormalities has traditionally utilized GTG-banding analysis, fluorescence in situ hybridization (FISH) assays, and multiplex ligation-dependent probe amplification. Microarray-based comparative genomic hybridization (array-CGH) is a relatively new technology that can identify microscopic and submicroscopic chromosomal imbalances. It has been proposed that an array with extended coverage at subtelomeric regions could characterize subtelomeric aberrations more efficiently in a single experiment. The targeted arrays for chromosome microarray analysis (CMA), developed by Baylor College of Medicine, have on average 12 BAC/PAC clones covering 10 Mb of each of the 41 subtelomeric regions. We screened 5,380 consecutive clinical patients using CMA. The most common reasons for referral included developmental delay (DD), and/or mental retardation (MR), dysmorphic features (DF), multiple congenital anomalies (MCA), seizure disorders (SD), and autistic, or other behavioral abnormalities. We found pathogenic rearrangements at subtelomeric regions in 236 patients (4.4%). Among these patients, 103 had a deletion, 58 had a duplication, 44 had an unbalanced translocation, and 31 had a complex rearrangement. The detection rates varied among patients with a normal karyotype analysis (2.98%), with an abnormal karyotype analysis (43.4%), and with an unavailable or no karyotype analysis (3.16%). Six patients out of 278 with a prior normal subtelomere-FISH analysis showed an abnormality including an interstitial deletion, two terminal deletions, two interstitial duplications, and a terminal duplication. In conclusion, genomic imbalances at subtelomeric regions contribute significantly to congenital disorders. Targeted array-CGH with extended coverage (up to 10 Mb) of subtelomeric regions will enhance the detection of subtelomeric imbalances, especially for submicroscopic imbalances.
PMCID: PMC2680131  PMID: 18663743
array-CGH; subtelomere; chromosomal abnormality; FISH
12.  Chronic Diarrhea and Skin Hyperpigmentation: A New Association 
The objective of this study was to describe patients with chronic diarrhea and abnormal skin hyperpigmentation with distinct distribution.
This is a retrospective review of children who presented with diarrhea and skin hyperpigmentation. The clinical presentation, laboratory investigations as well as endoscopic and histological data were reviewed.
Seven patients with chronic diarrhea had abnormal skin hyperpigmentation with distinct distribution and presented in the first two months of life. Six patients had other features such as abnormal hair and facial dysmorphism. Mental retardation was reported in one patient. Consanguinity was positive in six patients, and there was family history of consanguinity in four patients, with two patients being siblings. No significant immunodeficiency was reported. Intestinal biopsies were obtained in six patients and showed active chronic inflammation in three patients, partial villous atrophy in two patients, and eosinophilic infiltrate with mild villous atrophy in one patient. Colonic biopsies showed mild focal colitis in three patients and mild colitis with eosinophilic infiltrate in one patient. Skin biopsies showed a greater number of melanophagies with fibrosis of papillary derma in two patients but skin biopsy was normal in one patient. The hair of two patients was analyzed by electron microscopy, which showed an abnormal pattern with decreased pigmentation and diameter; however, its chemical analysis was normal. Two other patients had trichorrhexis nodosa, but no abnormalities were seen in one patient. Chromosomal number was normal in three patients. One patient died because of sepsis, and only one patient was dependent on total parenteral nutrition.
We believe that this association might represent a new syndrome with an autosomal recessive inheritance that warrants further studies.
PMCID: PMC2702934  PMID: 19568536
Diarrhea syndrome; phenotypic diarrhea; infantile diarrhea
13.  Molecular diagnostic testing for Klinefelter syndrome and other male sex chromosome aneuploidies 
Male sex chromosome aneuploidies are underdiagnosed despite concomitant physical and behavioral manifestations.
To develop a non-invasive, rapid and high-throughput molecular diagnostic assay for detection of male sex chromosome aneuploidies, including 47,XXY (Klinefelter), 47,XYY, 48,XXYY and 48,XXXY syndromes.
The assay utilizes three XYM and four XA markers to interrogate Y:X and X:autosome ratios, respectively. The seven markers were PCR amplified using genomic DNA isolated from a cohort of 323 males with aneuploid (n = 117) and 46,XY (n = 206) karyotypes. The resulting PCR products were subjected to Pyrosequencing, a quantitative DNA sequencing method.
Receiver operator characteristic (ROC) curves were used to establish thresholds for the discrimination of aneuploid from normal samples. The XYM markers permitted the identification of 47,XXY, 48,XXXY and 47,XYY syndromes with 100% sensitivity and specificity in both purified DNA and buccal swab samples. The 48,XXYY karyotype was delineated by XA marker data from 46,XY; an X allele threshold of 43% also permitted detection of 48,XXYY with 100% sensitivity and specificity. Analysis of X chromosome-specific biallelic SNPs demonstrated that 43 of 45 individuals (96%) with 48,XXYY karyotype had two distinct X chromosomes, while 2 (4%) had a duplicate X, providing evidence that 48,XXYY may result from nondisjunction during early mitotic divisions of a 46,XY embryo.
Quantitative Pyrosequencing, with high-throughput potential, can detect male sex chromosome aneuploidies with 100% sensitivity.
PMCID: PMC3411476  PMID: 22524164
Pyrosequencing; Sex chromosome aneuploidy; Klinefelter (47,XXY) syndrome; 47,XYY syndrome; 48,XXYY syndrome; 48,XXXY syndrome; Male infertility
14.  13q Deletion and central nervous system anomalies: further insights from karyotype–phenotype analyses of 14 patients 
Journal of Medical Genetics  2007;44(1):e60.
Chromosome 13q deletion is associated with varying phenotypes, which seem to depend on the location of the deleted segment. Although various attempts have been made to link the 13q deletion intervals to distinct phenotypes, there is still no acknowledged consensus correlation between the monosomy of distinct 13q regions and specific clinical features.
14 Italian patients carrying partial de novo 13q deletions were studied. Molecular–cytogenetic characterisation was carried out by means of array‐comparative genomic hybridisation (array‐CGH) or fluorescent in situ hybridisation (FISH).
Our 14 patients showed mental retardation ranging from profound–severe to moderate–mild: eight had central nervous system (CNS) anomalies, including neural tube defects (NTDs), six had eye abnormalities, nine had facial dysmorphisms and 10 had hand or feet anomalies. The size of the deleted regions varied from 4.2 to 75.7 Mb.
This study is the first systematic molecular characterisation of de novo 13q deletions, and offers a karyotype–phenotype correlation based on detailed clinical studies and molecular determinations of the deleted regions. Analyses confirm that patients lacking the 13q32 band are the most seriously affected, and critical intervals have been preliminarily assigned for CNS malformations. Dose‐sensitive genes proximal to q33.2 may be involved in NTDs. The minimal deletion interval associated with the Dandy–Walker malformation (DWM) was narrowed to the 13q32.2–33.2 region, in which the ZIC2 and ZIC5 genes proposed as underlying various CNS malformations are mapped.
PMCID: PMC2597907  PMID: 17209130
15.  Bilateral radial agenesis with absent thumbs, complex heart defect, short stature, and facial dysmorphism in a patient with pure distal microduplication of 5q35.2-5q35.3 
BMC Medical Genetics  2013;14:13.
A partial duplication of the distal long arm of chromosome 5 (5q35-- > qter) is known to be associated with a distinct phenotype referred to as Hunter-McAlpine syndrome. Clinical spectrum of this disorder mainly consists of mental retardation, microcephaly, short stature, skeletal anomalies, and craniofacial dysmorphism featuring flat facies, micrognathia, large, low-set dysplastic ears, hypertelorism, almond-shaped, down-slanted palpebral fissures, epicanthal folds, small nose, long philtrum, small mouth, and thin upper lip. Less frequent remarkable findings include craniosynostosis, heart defect, hypoplastic phalanges, preaxial polydactyly, hypospadias, cryptorchidism, and inguinal hernia. In most patients with a partial duplication of 5q the aberration occurred due to an inherited unbalanced translocation, therefore the phenotype was not reflective of pure trisomy 5q.
Case presentation
We report on a 9.5-year-old boy with some feature of Hunter-McAlpine syndrome including short stature, complex heart defect (dextrocardia, dextroversion, PFO), bilateral cryptorchidism, hypothyroidism, and craniofacial dysmorphism. Additionally, bilateral radial agenesis with complete absence of Ist digital rays, ulnar hypoplasia with bowing, choroidal and retinal coloboma, abnormal biliary vesicle were identified, which have never been noted in 5q trisomy patients. Karyotype analysis, sequencing and MLPA for TBX5 and SALL4 genes were unremarkable. Array comparative genomic hybridization detected a duplication on 5q35.2-5q35.3, resulting from a de novo chromosomal rearrangement. Our proband carried the smallest of all previously reported pure distal 5q trisomies encompassing terminal 5.4-5.6 Mb and presented with the most severe limb malformation attributed to the increased number of distal 5q copies.
We postulate that a terminal distal trisomy of 5q35.2-5q35.3, which maps 1.1 Mb telomeric to the MSX2 gene is causative for both radial agenesis and complex heart defect in our proband. A potential candidate gene causative for limb malformation in our proband could be FGFR4, which maps relatively in the closest position to the chromosomal breakage site (about 1.3 Mb) from all known 5q duplications. Since the limb malformation as well as the underlying genetic defect are distinct from other 5q trisomy patient we propose that a position effect resulting in altered long-range regulation of the FGFR4 (alternatively MSX2) may be responsible for the limb malformation in our proband.
PMCID: PMC3576294  PMID: 23342975
Pure distal trisomy 5q; Distal 5q duplication; Dup (5)(q35.2q35.3); Hunter-McAlpine syndrome; MSX2; FGFR4; Radial agenesis; Absent thumbs
16.  Value of computerised tomography in children with non-specific mental subnormally. 
Archives of Disease in Childhood  1982;57(5):381-383.
Seventy-six children had computerized tomography scans as part of an investigation of mental subnormality; most of them are severely retarded and all those over age 5 years attend special schools. Seventy-two per cent of the children had normal scans. Twenty per cent showed cerebral atrophy and in only 8% was there a specific abnormality (agenesis of corpus callosum, arachnoid cyst, communicating hydrocephalus). None of these findings had any positive prognostic implication. Sedation or general anaesthesia was required for all except one child. Injection pethidine compound was used for children under age 5 years or less than 30 kg in weight, and trimeprazine orally was used for older children. The radiation exposure was high--5.6 rad per scan, which is 100 times greater than that from a posteroanterior and lateral chest x-ray film. For these reasons computerised tomography scans cannot be recommended as a routine part of the investigation of children with non-specific mental subnormality.
PMCID: PMC1627556  PMID: 7092295
17.  A de novo 2.9 Mb interstitial deletion at 13q12.11 in a child with developmental delay accompanied by mild dysmorphic characteristics 
Molecular Cytogenetics  2014;7(1):92.
Proximal deletions in the 13q12.11 region are very rare. Much larger deletions including this region have been described and are associated with complex phenotypes of mental retardation, developmental delay and various others anomalies.
We report on a 3-year-old girl with a rare 2.9 Mb interstitial deletion at 13q12.11 due to a de novo unbalanced t(13;14) translocation. She had mild mental retardation and relatively mild dysmorphic features such as microcephaly, flat nasal bridge, moderate micrognathia and clinodactyly of 5th finger. Molecular karyotyping revealed a deletion on the long arm of chromosome 13 as involving sub-bands 13q12.11, a deletion of about 2.9 Mb.
The clinical application of array-CGH has made it possible to detect submicroscopical genomic rearrangements that are associated with varying phenotypes.The description of more patients with deletions of the 13q12.11 region will allow a more precise genotype-phenotype correlation.
PMCID: PMC4265435  PMID: 25506395
13q12.11; Array-CGH; Deletion; Mild dysmorphic features
18.  Ocular disorder in children with mental retardation 
Indian Journal of Psychiatry  2013;55(2):170-172.
Ocular problems are common in mentally retarded children. Due to population growth these problems are increasing. Prevalence rate is variable from region to region. Data on ocular problems in mentally retarded school children is lacking in this region.
The aim of the present study was to identify the ocular disorders in children with mental retardation attending special schools in a district and to study their relationship with the degree of retardation.
Materials and Methods:
A total of 241 mentally retarded school children in the age group of 6-16 years attending special schools for the mentally retarded children in a district in central India were examined by a team of ophthalmologist, psychiatrist, and a resident in ophthalmology department of a medical college. Complete ocular examination was done. Ocular problems were identified and categorized according to the intelligent quotient.
One hundred and twenty four children (51.45%) had ocular problems. Strabismus (10.37%) and refractive error (20.75%) were the common ocular problems seen in this study. An association was found between the severity of mental retardation and ocular problems (P<0.005). However, no association was seen between the severity of mental retardation and strabismus and refractive error.
A high prevalence of ocular problems was seen in mentally retarded school children. Children with mental retardation should undergo annual ophthalmological check up. Early detection and correction of ocular problems will prevent visual impairment in future.
PMCID: PMC3696242  PMID: 23825853
Children; mental retardation; ocular disorder; refractive error; strabismus
19.  Detection of chromosomal imbalances in children with idiopathic mental retardation by array based comparative genomic hybridisation (array-CGH) 
Journal of Medical Genetics  2005;42(9):699-705.
Chromosomal aberrations are a common cause of multiple anomaly syndromes that include growth and developmental delay and dysmorphism. Novel high resolution, whole genome technologies, such as array based comparative genomic hybridisation (array-CGH), improve the detection rate of submicroscopic chromosomal abnormalities allowing re-investigation of cases where conventional cytogenetic techniques, Spectral karyotyping (SKY), and FISH failed to detect abnormalities. We performed a high resolution genome-wide screening for submicroscopic chromosomal rearrangements using array-CGH on 41 children with idiopathic mental retardation (MR) and dysmorphic features. The commercially available microarray from Spectral Genomics contained 2600 BAC clones spaced at approximately 1 Mb intervals across the genome. Standard chromosome analysis (>450 bands per haploid genome) revealed no chromosomal rearrangements. In addition, multi-subtelomeric FISH screening in 30 cases and SKY in 11 patients did not detect any abnormality. Using array-CGH we detected chromosomal imbalances in four patients (9.8%) ranging in size from 2 to 14 Mb. Large scale copy number variations were frequently observed. Array-CGH has become an important tool for the detection of chromosome aberrations and has the potential to identify genes involved in developmental delay and dysmorphism. Moreover, the detection of genomic imbalances of clinical significance will increase knowledge of the human genome by performing genotype-phenotype correlation.
PMCID: PMC1736138  PMID: 16141005
20.  Partial monosomy 7q34-qter and 21pter-q22.13 due to cryptic unbalanced translocation t(7;21) but not monosomy of the whole chromosome 21: a case report plus review of the literature 
Autosomal monosomies in human are generally suggested to be incompatible with life; however, there is quite a number of cytogenetic reports describing full monosomy of one chromosome 21 in live born children. Here, we report a cytogenetically similar case associated with congenital malformation including mental retardation, motor development delay, craniofacial dysmorphism and skeletal abnormalities.
Initially, a full monosomy of chromosome 21 was suspected as only 45 chromosomes were present. However, molecular cytogenetics revealed a de novo unbalanced translocation with a der(7)t(7;21). It turned out that the translocated part of chromosome 21 produced GTG-banding patterns similar to original ones of chromosome 7. The final karyotype was described as 45,XX,der(7)t(7;21)(q34;q22.13),-21. As a meta analysis revealed that clusters of the olfactory receptor gene family (ORF) are located in these breakpoint regions, an involvement of OFR in the rearrangement formation is discussed here.
The described clinical phenotype is comparable to previously described cases with ring chromosome 21, and a number of cases with del(7)(q34). Thus, at least a certain percentage, if not all full monosomy of chromosome 21 in live-borns are cases of unbalanced translocations involving chromosome 21.
PMCID: PMC2442098  PMID: 18564437
21.  Otolaryngologic markers for the early diagnosis of Turner syndrome 
To identify and characterize otolaryngologic markers for the early diagnosis of Turner Syndrome (TS).
Study Design
Prospective cohort survey.
Clinical Center of the National Institutes of Health (NIH).
Ninety-one females, 7 - 61 years old (average = 28.7 y), enrolled in a multidisciplinary study of karyotype-phenotype correlations in TS.
Main Outcome Measures
Age at diagnosis, X chromosome karyotype, history of chronic or recurrent otitis media (OM), sensorineural hearing loss (SNHL), palate dysmorphism, pinna deformity, pterygium colli, low posterior hairline, low-set ears, and micrognathia.
Sixty-nine (76%) patients had a history of chronic or recurrent OM, 62 (68%) had a dysmorphic palate, 57 (63%) had SNHL, and 90 (99%) had one or more of these findings. 83 (91%; average age at diagnosis = 9.4 y) had one or more external craniofacial signs: pinna abnormalities, pterygium colli, low-set ears, micrognathia or a low posterior hairline. Eight patients (average age at diagnosis = 13.2 y) had no external craniofacial signs, although seven (88%) of these eight patients had a history of chronic or recurrent OM, dysmorphic palate or SNHL. The age at diagnosis was not significantly different between groups with or without external craniofacial signs (P = 0.126).
Patients with mild or incompletely penetrant TS phenotypes often present with otitis media, hearing loss, or both before the diagnosis of TS is established. Palatal dysmorphism, including ogival morphology, is another otolaryngologic marker for TS. Prompt recognition of these manifestations of TS could hasten its diagnosis and appropriate medical care.
PMCID: PMC2757481  PMID: 19732968
22.  Screening for submicroscopic chromosome rearrangements in children with idiopathic mental retardation using microsatellite markers for the chromosome telomeres 
Journal of Medical Genetics  1999;36(5):405-411.
Recently much attention has been given to the detection of submicroscopic chromosome rearrangements in patients with idiopathic mental retardation. We have screened 27 subjects with mental retardation and dysmorphic features for such rearrangements using a genetic marker panel screening. The screening was a pilot project using markers from the subtelomeric regions of all 41 chromosome arms. The markers were informative for monosomy in both parents at 366/902 loci (40.6%, 95% confidence interval 37.0-44.2%) in the 22 families where DNA was available from both parents. In two of the 27 subjects, submicroscopic chromosomal aberrations were detected. The first patient had a 5-6 Mb deletion of chromosome 18q and the second patient had a 4 Mb deletion of chromosome 1p. The identification of two deletions in 27 cases gave an aberration frequency of 7.5% without adjustment for marker informativeness (95% confidence interval 1-24%) and an estimated frequency of 18% if marker informativeness for monosomy was taken into account. This frequency is higher than previous estimates of the number of subtelomeric chromosome abnormalities in children with idiopathic mental retardation (5-10%) although the confidence interval is overlapping. Our study suggests that in spite of the low informativeness of this pilot screening, submicroscopic chromosome aberrations may be a common cause of dysmorphic features and mental retardation.

Keywords: idiopathic mental retardation; submicroscopic chromosome rearrangement; chromosome telomeres; 1p monosomy
PMCID: PMC1734367  PMID: 10353788
23.  Klinefelter syndrome and other sex chromosomal aneuploidies 
The term Klinefelter syndrome (KS) describes a group of chromosomal disorder in which there is at least one extra X chromosome to a normal male karyotype, 46,XY. XXY aneuploidy is the most common disorder of sex chromosomes in humans, with prevalence of one in 500 males. Other sex chromosomal aneuploidies have also been described, although they are much less frequent, with 48,XXYY and 48,XXXY being present in 1 per 17,000 to 1 per 50,000 male births. The incidence of 49,XXXXY is 1 per 85,000 to 100,000 male births. In addition, 46,XX males also exist and it is caused by translocation of Y material including sex determining region (SRY) to the X chromosome during paternal meiosis. Formal cytogenetic analysis is necessary to make a definite diagnosis, and more obvious differences in physical features tend to be associated with increasing numbers of sex chromosomes. If the diagnosis is not made prenatally, 47,XXY males may present with a variety of subtle clinical signs that are age-related. In infancy, males with 47,XXY may have chromosomal evaluations done for hypospadias, small phallus or cryptorchidism, developmental delay. The school-aged child may present with language delay, learning disabilities, or behavioral problems. The older child or adolescent may be discovered during an endocrine evaluation for delayed or incomplete pubertal development with eunuchoid body habitus, gynecomastia, and small testes. Adults are often evaluated for infertility or breast malignancy. Androgen replacement therapy should begin at puberty, around age 12 years, in increasing dosage sufficient to maintain age appropriate serum concentrations of testosterone, estradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH). The effects on physical and cognitive development increase with the number of extra Xs, and each extra X is associated with an intelligence quotient (IQ) decrease of approximately 15–16 points, with language most affected, particularly expressive language skills.
PMCID: PMC1634840  PMID: 17062147
24.  Identification of an unbalanced cryptic translocation t(9;17)(q34.3;p13.3) in a child with dysmorphic features 
Journal of Medical Genetics  1995;32(10):819-822.
We report a case of an unbalanced cryptic telomeric translocation 46,XY,der(17),t(9;17)(q34.3;p13.3) in a boy with dysmorphic features and developmental delay. The proband had intrauterine growth retardation, postnatal short stature, and mild microcephaly. Magnetic resonance imaging showed incomplete myelination, but no evidence of lissencephaly. Cytogenetic analysis of the proband's peripheral blood showed an abnormal 17p. Fluorescence in situ hybridisation (FISH) with a Miller-Dieker cosmid probe did not detect a deletion for that area. Further analysis with a 17p telomere specific probe identified an unbalanced telomeric translocation. The same probe was used to determine the presence of an apparent balanced translocation t(9;17)(q34.3;p13.3) in the mother of the proband. The balanced translocation was confirmed with two cosmids that map distally on 9q34.3. Two phenotypically normal half sibs, a maternal aunt, a maternal uncle, and the maternal grandmother were found to be balanced translocation carriers as well. A subtle translocation carriers as well. A subtle translocation is one mechanism that can produce an abnormal phenotype in a patient who had a normal karyotype at lower band resolution levels.
PMCID: PMC1051710  PMID: 8558564
25.  Risk factors for mental retardation. 
Archives of Disease in Childhood  1985;60(10):946-952.
Risk factors for mental retardation were studied prospectively in 12 000 children born in northern Finland in 1966 and followed to the age of 14 years. The number of untraced children was less than 2 per 1000. Altogether 326 children had an IQ less than 86, and the incidence of severe retardation (IQ less than 50) was especially high. An incidence figure for children with mental retardation, a separate figure for healthy children, and also the death rate were calculated for each disease. Only in the cases of Down's syndrome and some hereditary diseases were all the exposed children mentally retarded; in other diseases some children did not seem to suffer any sequelae. A risk factor could be found for 50.6% of the total number of children with mental retardation, the percentage decreasing from the severest to the mildest form (86.7%, 45.4%, and 30.9%). Some 9.4% of the healthy children and 77.7% of those who died had had one or more of these conditions. Prenatal conditions were most often associated with severe mental retardation (64%), and perinatal conditions with mild retardation, (IQ 50 to 70; 27%) and mental subnormality (IQ 71 to 85; 18%). Cases with no known risk factor were more common among boys than girls.
PMCID: PMC1777517  PMID: 3840671

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