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The chance of a male with severe oligozoospermia or azoospermia achieving a pregnancy has undergone a revolutionary increase with the introduction of the intracytoplasmic sperm injection technique (ICSI). However, since ICSI circumvents part of the natural sperm selection mechanisms, the possible transmission of genetic defects to the offspring is a major concern. Cytogenetic analysis is a relatively simple technique to identify at least the carriers of a chromosomal aberration before starting the ICSI procedure. In order to assess the frequency of chromosomal aberrations in male ICSI candidates, we have performed a nationwide cytogenetic study. Of the 1792 males examined, 72 (4.0%) revealed a chromosomal aberration, and one individual even had two. Numerical sex chromosomal aberrations and Robertsonian translocations predominated, followed by reciprocal translocations, inversions and supernumerary marker chromosomes. The different implications, in case a chromosomal aberration is encountered prior to ICSI, are discussed. [ABSTRACT FROM AUTHOR]

A follow-up study was performed to investigate the impact of the detection of a chromosome abnormality in infertile men who are candidates for intracytoplasmic sperm injection (ICSI) treatment. In this collaborative study between clinical genetics centres and fertility clinics in the Netherlands, 75 ICSI couples of which the male partners had a chromosome abnormality were included. All couples were extensively counselled on the risk of having a chromosomally unbalanced child. Forty-two out of 75 couples chose to proceed with the ICSI treatment. So far, treatment has resulted in a pregnancy in 11 cases. Four of them opted to have invasive prenatal diagnosis. Despite the genetic risks related to a chromosome abnormality in infertile men, a small majority (56%) of the couples did not refrain from the ICSI treatment. [ABSTRACT FROM AUTHOR]

We report a case of del(9)(q22q32) in a severely mentally retarded boy. The most prominent clinical features are short stature, microcephaly, dysmorphic facies, and delayed bone age. Although six cases of this deletion have now been reported, confirmation of a definite syndrome is not yet possible. [ABSTRACT FROM PUBLISHER]

Background: Medical students need to be trained in delivering diversity-responsive health care but unknown is what competencies teachers need. The aim of this study was to devise a framework of competencies for diversity teaching., Methods: An open-ended questionnaire about essential diversity teaching competencies was sent to a panel. This resulted in a list of 74 teaching competencies, which was sent in a second round to the panel for rating. The final framework of competencies was approved by the panel., Results: Thirty-four experts participated. The final framework consisted of 10 competencies that were seen as essential for all medical teachers: (1) ability to critically reflect on own values and beliefs; (2) ability to communicate about individuals in a nondiscriminatory, nonstereotyping way; (3) empathy for patients regardless of ethnicity, race or nationality; (4) awareness of intersectionality; (5) awareness of own ethnic and cultural background; (6) knowledge of ethnic and social determinants of physical and mental health of migrants; (7) ability to reflect with students on the social or cultural context of the patient relevant to the medical encounter; (8) awareness that teachers are role models in the way they talk about patients from different ethnic, cultural and social backgrounds; (9) empathy for students of diverse ethnic, cultural and social background; (10) ability to engage, motivate and let all students participate., Conclusions: This framework of teaching competencies can be used in faculty development programs to adequately train all medical teachers.

Background: The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome., Methods: We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function., Results: We identified a single heterozygous missense variant, c.1337A>G (p.Tyr446Cys), in transducin β-like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome., Conclusions: This study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11-Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with β-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P=0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.

Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by amelogenesis imperfecta, psychomotor delay or regression and seizures starting early in childhood. KTS was established as a distinct clinical entity after the first report by Kohlschütter in 1974, and to date, only a total of 20 pedigrees have been reported. The genetic etiology of KTS remained elusive until recently when mutations in ROGDI were independently identified in three unrelated families and in five likely related Druze families. Herein, we report a clinical and genetic study of 10 KTS families. By using a combination of whole exome sequencing, linkage analysis, and Sanger sequencing, we identify novel homozygous or compound heterozygous ROGDI mutations in five families, all presenting with a typical KTS phenotype. The other families, mostly presenting with additional atypical features, were negative for ROGDI mutations, suggesting genetic heterogeneity of atypical forms of the disease., (© 2012 Wiley Periodicals, Inc.)

The correct interpretation of copy number gains in patients with developmental delay and multiple congenital anomalies is hampered by the large number of copy number variations (CNVs) encountered in healthy individuals. The variable phenotype associated with copy number gains makes interpretation even more difficult. Literature shows that inheritence, size and presence in healthy individuals are commonly used to decide whether a certain copy number gain is pathogenic, but no general consensus has been established. We aimed to develop guidelines for interpreting gains detected by array analysis using array CGH data of 300 patients analysed with the 105K Agilent oligo array in a diagnostic setting. We evaluated the guidelines in a second, independent, cohort of 300 patients. In the first 300 patients 797 gains of four or more adjacent oligonucleotides were observed. Of these, 45.4% were de novo and 54.6% were familial. In total, 94.8% of all de novo gains and 87.1% of all familial gains were concluded to be benign CNVs. Clinically relevant gains ranged from 288 to 7912 kb in size, and were significantly larger than benign gains and gains of unknown clinical relevance (P < 0.001). Our study showed that a threshold of 200 kb is acceptable in a clinical setting, whereas heritability does not exclude a pathogenic nature of a gain. Evaluation of the guidelines in the second cohort of 300 patients revealed that the interpretation guidelines were clear, easy to follow and efficient.

High-resolution genome-wide array analysis enables detailed screening for cryptic and submicroscopic imbalances of microscopically balanced de novo rearrangements in patients with developmental delay and/or congenital abnormalities. In this report, we added the results of genome-wide array analysis in 54 patients to data on 117 patients from seven other studies. A chromosome imbalance was detected in 37% of all patients with two-breakpoint rearrangements. In 49% of these patients, the imbalances were located in one or both breakpoint regions. Imbalances were more frequently (90%) found in complex rearrangements, with the majority (81%) having deletions in the breakpoint regions. The size of our own cohort enabled us to relate the presence of an imbalance to the clinical features of the patients by using a scoring system, the De Vries criteria, that indicates the complexity of the phenotype. The median De Vries score was significantly higher (P=0.002) in those patients with an imbalance (5, range 1-9) than in patients with a normal array result (3, range 0-7). This study provides accurate percentages of cryptic imbalances that can be detected by genome-wide array analysis in simple and complex de novo microscopically balanced chromosome rearrangements and confirms that these imbalances are more likely to occur in patients with a complex phenotype.

Aims: Holt-Oram syndrome (HOS) is a heart/hand syndrome clinically characterized by upper limb and cardiac malformations. Mutations in T-box transcription factor 5 (TBX5) underlie this syndrome, the majority of which lead to premature stops. In this study, we present our functional analyses of five (novel) missense TBX5 mutations identified in HOS patients, most of whom presented with severe cardiac malformations., Methods and Results: Functional characterization of mutant proteins shows a dramatic loss of DNA-binding capacity, as well as diminished binding to known cardiac interaction partners NKX2-5 and GATA4. The disturbance of these interactions leads to a loss of function, as measured by the reduced activation of Nppa and FGF10 in rat heart derived cells, although with variable severity. Two out of the five mutations are peculiar: one, p.H220del, is associated with additional extra-cardiac defects, perhaps by interfering with other T-box dependant pathways, and another, p.I106V, leads to limb defects only, which is supported by its normal interaction with cardiac-specific interaction partners., Conclusion: Overall, our data are consistent with the hypothesis that these novel missense mutations in TBX5 lead to functional haploinsufficiency and result in a reduced transcriptional activation of target genes, which is likely central to the pathogenesis of HOS.

Polymicrogyria (PMG) is a brain malformation due to abnormal cortical organisation. It is a heterogeneous disorder associated with 22q11.2 deletion syndrome (also known as velocardiofacial (VCF) syndrome) amongst others. Since this association was first recognised in 1996, over 30 patients with PMG and 22q11.2 deletion have been described. In 22q11.2 deletion syndrome, PMG is mainly located in the perisylvian areas; it frequently has an asymmetrical presentation with a striking predisposition for the right hemisphere. Neurological features of perisylvian PMG include developmental delay/mental retardation, seizures, microcephaly, spasticity and oromotor dysfunction. Thus in children diagnosed with 22q11.2 deletion syndrome, a finding of PMG has important prognostic value. We present a seven-month old boy with microcephaly, short stature and developmental delay. A cerebral MRI showed slightly enlarged ventricles and symmetrical perisylvian polymicrogyria. A 22q11.2 deletion was revealed by array-based comparative genomic hybridization. Remarkably the boy had no other manifestations of VCF syndrome. Paediatricians, child neurologists and clinical geneticists should be aware that the presence of PMG (especially in the perisylvian areas) needs investigating for 22q11.2 deletion, even if other more common VCF syndrome features are absent., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

We report on a male patient with intra-uterine growth retardation, microcephaly, coloboma, laryngomalacia and developmental delay. Array CGH analysis revealed a 649 kb duplication on chromosome 1p34.1. Only five patients with overlapping duplications have been reported thus far. Ten known genes are located in the duplicated region, including the POMGNT1 gene encoding for O-mannose beta-1,2-N-acetylglucosaminyltransferase. This gene, mutated in muscle-eye-brain disease, might be causative for the observed phenotype in our patient.

Behavioural differences have been described in patients with type I deletions (between breakpoints 1 and 3 (BP1-BP3)) or type II deletions (between breakpoints 2 and 3) of the 15q11.2 Prader-Willi/Angelman region. The larger type I deletions appear to coincide with more severe behavioural problems (autism, ADHD, obsessive-compulsive disorder). The non-imprinted chromosomal segment between breakpoints 1 and 2 involves four highly conserved genes, TUBGCP5, NIPA1, NIPA2, and CYFIP1; the latter three are widely expressed in the central nervous system, while TUBGCP5 is expressed in the subthalamic nuclei. These genes might explain the more severe behavioural problems seen in type I deletions. We describe nine cases with a microdeletion at 15q11.2 between BP1-BP2, thus having a haploinsufficiency for TUBGCP5, NIPA1, NIPA2, and CYFIP1 without Prader-Willi/Angelman syndrome. The clinical significance of a pure BP1-BP2 microdeletion has been debated, however, our patients shared several clinical features, including delayed motor and speech development, dysmorphisms and behavioural problems (ADHD, autism, obsessive-compulsive behaviour). Although the deletion often appeared to be inherited from a normal or mildly affected parent, it was de novo in two cases and we did not find it in 350 healthy unrelated controls. Our results suggest a pathogenic nature for the BP1-BP2 microdeletion and, although there obviously is an incomplete penetrance, they support the existence of a novel microdeletion syndrome in 15q11.2.

We report on a 6-year-old girl with linear streaks of apparent hypopigmentation and hyperpigmentation following the Blaschko lines, growth retardation, bupthalmos of the left eye, and mild mental retardation. She had a 45,X karyotype in lymphocytes. In cultured fibroblasts a double aneuploidy mosaicism was detected, consisting of a cell line with trisomy for chromosome 7 and a cell line with monosomy for the X-chromosome and no cell line with a normal karyotype. Cutis tricolor or three levels of pigmentation in different skin areas suggested presence of a third, probably normal cell line. Double aneuploidy mosaicism of a cell line with monosomy X and a cell line with trisomy of an autosome is a rare finding. The combination of monosomy X with trisomy of chromosomes 8, 10, 13, 18, and 21 has been reported, but not the combination with trisomy 7. In the 45,X cell line, microsatellite analysis showed loss of the maternal X-chromosome, and presence of a maternal and paternal chromosome 7. The 47,XX,+7 cell line showed a paternal and a maternal X-chromosome, and a paternal and two identical maternal chromosomes 7. Mechanisms that might explain this double aneuploidy mosaicism are discussed., ((c) 2005 Wiley-Liss, Inc.)

In 1998, Pierpont et al. reported on two unrelated boys with plantar lipomatosis, unusual facial phenotype, and developmental delay as a possible new MR/MCA syndrome. Here we report on a 2-year-old boy with similar manifestations: axial hypotonia in the first few months, prolonged feeding problems, moderate developmental delay, no speech development, deep palmar and plantar grooves, fat pads at the anteromedial aspect of the heels, and a distinct facial phenotype (high forehead, high anterior hairline, mild midfacial hypoplasia, remarkably narrow and upward slanted palpebral fissures, broad nasal ridge and tip, broad philtrum, bowed upper lip, "pouting" lower lip, full cheeks, and flat occiput). Brain MRI and MR spectroscopy studies showed relatively small frontal lobes, some widening of the lateral and third ventricles, and increased choline levels in the frontal white matter. Cytogenetic studies in lymphocytes and skin fibroblasts and whole genome micro-array CGH failed to show abnormalities. The present patient has a phenotype almost identical to that of the earlier reported children (Pierpont et al. [1998]: Am J Med Genet 75:18-21), which thereby validates this as a separate MR/MCA syndrome, appropriately designated Pierpont syndrome. The cause of the entity remains uncertain, the most likely etiologies being X-linked recessive or autosomal dominant genes., (Copyright 2005 Wiley-Liss, Inc.)

Toriello and Carey [1988: Am J Med Genet 31:17-23] first described a syndrome with component manifestations of corpus callosum agenesis, unusual facial appearance, Robin sequence, and other anomalies. This was termed the Toriello-Carey syndrome by Lacombe et al. [1992: Am J Med Genet 42:374-376]. Since then, 11 reports describing 16 additional children have been published; in addition, we have had the opportunity to review over 30 unpublished cases. However, for various reasons, only 25 of the unpublished patients were included in this review. Based on this total, we can begin to better delineate this syndrome, as well as provide some information on natural history., (Copyright 2003 Wiley-Liss, Inc.)

We report a prenatal case of a maternally inherited abnormal chromosome 16, originally interpreted as a pericentric inversion only, but after family studies re-interpreted as a pericentric inversion (16) accompanied by an unbalanced (7;16) translocation. Because of the inversion 16 and an elder son with developmental delay and craniofacial dysmorphic features, in the past karyotyped as 46,XY, the chromosomes 16 of the mother and son were carefully re-examined. Using a whole chromosome 16 paint and sub-telomere probes of 16p and 16q, the karyotype of the mother was shown to be 46,XX,inv(16)(p11.2q23.2).ish t(7;16)(q36;p13.3)inv(16). Subsequently one chromosome 16 of the elder son appeared to be a der(16)t(7;16)(q36;p13.3). This is probably the result of a meiotic crossover between the chromosomes 16 in the mother. The prenatal karyotype was finally interpreted as 46,XY,inv(16)(p11.2q23.2).ish der(16)t(7;16)(q36;p13.3)inv(16). This is the same cytogenetic imbalance as his elder brother: a partial trisomy of chromosome 7 (q36-->qter) and a partial monosomy of chromosome 16 (p13.3-->pter)., (Copyright 2001 John Wiley & Sons, Ltd.)

We report on a boy with a maternal uniparental disomy for chromosome 14 (UPD(14)). At 7 years of age he was referred to us by the paediatrician because of symptoms of Prader-Willi syndrome (PWS). He showed short stature, obesity, mild developmental delay, cryptorchidism, and some mild dysmorphic features. The history further indicated intrauterine growth retardation at the end of the pregnancy. His mother was 44 years of age at the time of his birth. After birth he showed hypotonia with poor sucking, for which gavage feeding was needed. Motor development was delayed. After 1 year he became obese despite a normal appetite. Recurrent middle ear infections, a high pain threshold, and a great skill with jigsaw puzzles were reported. There were no behavioural problems or sleep disturbance. Chromosomal analysis was normal (46,XY). DNA analysis for Prader-Willi syndrome showed no abnormalities. Two years later he was re-examined because we thought his features fitted the PWS-like phenotype associated with maternal UPD(14). At that time precocious puberty was evident. DNA analysis showed maternal heterodisomy for chromosome 14. In all the previously described 11 cases with maternal UPD(14), a Robertsonian translocation involving chromosome 14 was detected cytogenetically before DNA analysis. This is the first report of diagnosis of maternal UPD(14) based on clinical features. This finding underlines the importance of DNA analysis for maternal UPD(14) in patients with a similar PWS-like phenotype even without previous identification of a Robertsonian translocation involving chromosome 14.

Mosaicism for a balanced reciprocal translocation (BRTM) is rare. As far as we know only 26 cases of BRTM, demonstrated in lymphocyte cultures, have been described, five of which had an abnormal phenotype. Prenatally three confirmed cases with a normal phenotypic outcome have been described. Here we present three further cases of BRTM in lymphocyte cultures. The first was detected during a family study, the second after an abnormal karyotype in chorionic villus sampling, and the third because of a history of stillborn children. All three carriers have normal phenotypes. An inventory of the BRTM cases reported so far is made.

A low level of high density lipoprotein (HDL) cholesterol is a strong predictor of ischaemic heart disease (IHD) and myocardial infarction. One cause of low HDL-cholesterol is Tangier disease (TD), an autosomal codominant inherited condition first described in 1961 in two siblings on Tangier Island in the United States of America. Apart from low HDL-cholesterol levels and an increased incidence of atherosclerosis, TD is characterized by reduced total cholesterol, raised triglycerides, peripheral neuropathy and accumulation of cholesteryl esters in macrophages, which causes enlargement of the liver, spleen and tonsils. In contrast to two other monogenic HDL deficiencies in which defects in the plasma proteins apoA-I and LCAT interfere primarily with the formation of HDL (refs 7-10), TD shows a defect in cell signalling and the mobilization of cellular lipids. The genetic defect in TD is unknown, and identification of the Tangier gene will contribute to the understanding of this intracellular pathway and of HDL metabolism and its link with IHD. We report here the localization of the genetic defect in TD to chromosome 9q31, using a genome-wide graphical linkage exclusion strategy in one pedigree, complemented by classical lod score calculations at this region in a total of three pedigrees (combined lod 10.05 at D9S1784). We also provide evidence that TD may be due to a loss-of-function defect.

We describe a boy and his father with the chorioretinal dysplasia-microcephaly-mental retardation syndrome (CDMMS). Our report extends the phenotypic spectrum of autosomal dominant CDMMS by describing microphthalmia for the first time in an autosomal dominant family. The boy was also severely mentally retarded in contrast to the usual mild mental retardation in AD-CDMMS. Furthermore he had hypertonia, dysmorphic features and low body weight, which are uncommon in AD-CDMMS. CDMMS is a rare disorder. We traced 18 reports on CDMMS including 10 families, 6 with horizontal transmission and 4 with vertical transmission. There are 8 reports and observations on isolated cases with CDMMS. This might imply genetic heterogeneity with autosomal recessive and autosomal dominant inheritance, with a more severe clinical picture in the former but with quite variable inter- and intrafamilial expression. A review of the literature is given. The existence of autosomal recessive inheritance in families with so-called horizontal transmission is discussed as variable expression, reduced penetrance and germline mosaicism may also explain this condition. Careful (particularly ophthalmologic) examination of first degree relatives is necessary before genetic counseling is given.