Fertility in patients with X chromosome deletions

Three fertile, non-mosaic patients with partial monosomy of an X-chromosome (two with Xp deletion with breakpoints at Xpl 106 and Xp2101, respectively, and one with a del(Xq25)) were found among 12 females with Xp deletion and three with Xq deletion investigated in this laboratory after the advent of banding techniques. Four phenotypically normal children resulted from a total of seven pregnancies in these women. Three of the children were chromosomally normal and one girl presented the same del(Xp) as her mother. The possibility of having genotypically and phenotypically normal offspring should be taken into account in the management and genetic counseling of children and females with X-chromosome deletions.     

Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation

Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1. ARHGEF9 alterations, some inherited from unaffected mothers, have been reported in males with autism, seizures and severe neurodevelopmental abnormalities. In females, a spectrum of mild to moderate phenotype has been detected. We report two unrelated females with autism and mild intellectual disability. High resolution X-chromosome microarray analysis revealed de novo intragenic deletions in ARHGEF9 of 24?kb and 56?kb involving exons 5–8 and exons 3–8 and leading to truncated forms of collybistin. Peripheral blood samples revealed random X-chromosome inactivation in both patients. To explain phenotypic variability in female patients, we propose a model for disruption of collybistin and various irregular interactions in post-synaptic neurons based on X inactivation patterns. Our findings highlight the importance of ARHGEF9 integrity and suggest further research on its correlation with autism and neurobehavioral problems.     

DNA polymorphism of the RC8 probe on the X-chromosome: Identification of a new DNA variant with the Taql enzyme

Restriction fragment length polymorphisms detectable with the RC8 probe, a probe for an area located on the short arm of the X-chromosome, and loosely linked to the locus for Duchenne muscular dystrophy, have been studied in a Norwegian population. With the TaqI enzyme three variants were observed. The gene frequencies of the previously detected variants were 0.867 and 0.082, respectively, and the frequency of a new variant was 0.051. Family studies confirmed Mendelian inheritance of the variants.     

Paternal deletion 6q24.3: a new congenital anomaly syndrome associated with intrauterine growth failure, early developmental delay and characteristic facial appearance

Deletions of the long arm of chromosome 6 are relatively uncommon and to date minimal genotype-phenotype correlations have been observed. We report on three unrelated patients with de novo paternal interstitial deletions of 6q24.3. FISH mapping was used to delineate the minimal region of overlap between these three patients. Although all three patients had different size deletions and different breakpoints, two of the patients shared a 2.5 Mb region of overlap and strikingly similar facial features including a triangular face, frontal bossing with metopic prominence, short and upward-slanting palpebral fissures, asymmetry of upper eyelids, hooded eyelids, shallow orbits, prominent inferior orbital crease, wide mouth, and long and flat philtrum. They also had redundant skin, joint laxity, a small thorax, and early developmental delay. The smallest region of overlap between all three patients was a region of deletion less than 1 Mb; all had a history of IUGR and postnatal short stature without overt radiologic skeletal anomalies. The dysmorphic features, early developmental and growth delay may be due to the hemizygous state for one of the genes in the deleted region of two of the patients or to a long range effect of the deletion on expression of other genes. In addition, since imprinted genes have been reported in this region, paternal deletion of an imprinted gene in all three patients may contribute to the growth phenotype. We propose that this is a new congenital malformation syndrome associated with a paternal deletion of 6q24.3.     

Deletions of different segments of the long arm of chromosome 4

We report the clinical and chromosomal findings in 8 patients with deletions of the long arm of chromosome 4. Four of these patients appear to have terminal deletions beginning in band 4q31, and therefore, lack the digital 1/3 of the long arm of chromosome 4. We confirm that deletion of 4q31→qter causes a recognizable syndrome, and we further define the phenotype of that syndrome. A 5th patient has a shorter terminal deletion, ie, 4q33→qter. This deletion causes a milder phenotypic expression than that seen in the severe 4q terminal-deletion syndrome. The remaining 3 patients have interstitial deletions of the long arm of the 4th chromosome, including segments 4q21.1→q25, 4q21.3→q26, and 4q27→q31.3. The phenotypic expression noted in these patients is variable and differs from the 4q terminal-deletion syndrome.     

Deletion of the long arm of chromosome 11 [46, XX, deI(11)(q24.1 → qter)]

A child who presented at three months of age with pyloric stenosis and pancytopenia was found to have a partial deletion of the long arm of chromosome 11, del(11)(q24.1----qter). Only two previous cases have been described with an apparently identical chromosomal deletion, and both exhibit similar phenotypic features. Other patients with larger deletions of the distal region of the long arm of chromosome 11 show many features in common with these three cases. It is suggested that the region of the long arm of chromosome 11 from band q24.1 to qter may contain the genetic material responsible for the expression of the 11q - phenotype.     

X-linked hypohidrotic ectodermal dysplasia. Genetic and dental findings in 67 Danish patients from 19 families

This study aimed to investigate genotype and phenotype in males affected with X-linked hypohidrotic ectodermal dysplasia (HED) and in female carriers, to analyse a possible genotype–phenotype correlation, and to analyse a possible relation between severity of the symptoms and the X-chromosome inactivation pattern in female carriers. The study group comprised 67 patients from 19 families (24 affected males and 43 female carriers). All participants had clinical signs of ectodermal dysplasia and a disease-causing EDA mutation. The EDA gene was screened for mutations by single-stranded conformational polymorphism and direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) analysis was used to detect deletions/duplications in female probands. Sixteen different EDA mutations were detected in the 19 families, nine not described previously. The MLPA analysis detected a deletion of exon 1 in one female proband. No genotype–phenotype correlations were observed, and female carriers did not exhibit a skewed X-chromosome inactivation pattern. However, in two female carriers with pronounced clinical symptoms, in whom the parental origin of each allele was known, we observed that mainly the normal allele was inactivated.     

Delineation of a critical region on chromosome 18 for the del(18)(q12.2q21.1) syndrome

Deletions involving the long arm of chromosome 18 have been reported in many patients. Most of these deletions are localized in the distal half of the long arm (18q21.1 --> qter) and are detectable by standard cytogenetic analysis. However, smaller interstitial deletions leading to a recognizable phenotype and residing in the region around chromosome band 18q12.3 (bands q12-q21) are less common. Here we report on an interstitial deletion of less than 1.8 Mb within chromosomal band 18q12.3. The phenotypic features of the propositus correspond well with those observed in patients with larger cytogenetically detectable deletions encompassing chromosome band 18q12.3. The deletion enabled us to define a critical region for the following features of the del(18)(q12.2q21.1) syndrome: hypotonia, expressive language delay, short stature, and behavioral problems.     

Submicroscopic deletion in 14q32.3 through a de novo tandem translocation between 14q and 21p

We describe a male child with craniofacial anomalies, postnatal onset growth retardation, microcephaly, multiple minor anomalies, hearing loss, and moderate delay of mental and statomotor development. He carries a previously undescribed tandem translocation between the long arm of chromosome 14 and the short arm of chromosome 21 that arose de novo. As proven by fluorescence in situ hybridization a microdeletion not detectable with high-resolution G-banding occured in 14q32.3, the terminal band on the long arm of chromosome 14. The resulting phenotype includes most abnormalities encountered in patients with terminal 14q32.3 deletions but in addition includes some characteristics of the ring chromosome 14 syndrome. Am. J. Med. Genet. 80:443–447, 1998. © 1998 Wiley-Liss, Inc.     

Multiple hemangiomas in a patient with a t(3q;4p) translocation: an infrequent association with Wolf-Hirschhorn syndrome

We report on the clinical phenotype of an infant with a duplication of the terminal portion of the long arm of chromosome 3(q26.3-qter) and a deletion of the terminal portion of the short arm of chromosome 4(p16.3) with multiple hemangiomas and a hamartoma. Patients with deletions of distal 4p have the characteristic features of Wolf-Hirschhorn syndrome (WHS); whereas those with the distal duplication of 3q have a well recognized syndrome with some features resembling Cornelia-de Lange syndrome (CdLS). Neither of these recognized chromosomal anomalies has been reported previously to be associated with multiple hemangiomas or other vascular malformations.     

Interstitial and terminal deletions of the long arm of chromosome 4: further delineation of phenotypes

We reviewed 45 patients with a deletion of the long arm of chromosome 4. Forty-one were previous reports (25 terminal deletions and 16 interstitial deletions) and 4 are new cases with terminal deletions. Of the 29 patients with terminal deletions, 18 with deletion at 4q31 and 4 at 4q32----qter had an identifiable phenotype consisting of abnormal skull shape, hypertelorism, cleft palate, apparently low-set abnormal pinnae, short nose with abnormal bridge, virtually pathognomonic pointed fifth finger and nail, congenital heart and genitourinary defects, moderate-severe mental retardation, poor postnatal growth, and hypotonia. Six patients with a deletion at 4q33 and one patient with deletion 4q34 were less severely affected. In general, patients with various interstitial deletions proximal to 4q31 had a phenotype that was less specific, although mental retardation and minor craniofacial anomalies were also present. There were 3 patients with piebaldism and one with Rieger syndrome. We conclude that terminal deletion of chromosome 4q (4q31----qter) appears to produce a distinctive malformation (MCA/MR) syndrome in which the phenotype correlates with the amount of chromosome material missing and which differs from the more variable phenotype associated with interstitial deletions of 4q.     

Proximal deletions of the long arm of the Y chromosome suggest a critical region associated with a specific subset of characteristic Turner stigmata

Turner syndrome is a complex human disorder that generally associatesa 45, X karyotype to a female phenotype presenting with gonadaldysgenesis, short stature and a number of characteristic somaticfeatures. It has been hypothesised that this specific phenotypewas the consequence of the haploinsuffic-iency of some X-linkedgenes having functional homologs on the Y chromosome. Here wedescribe four patients with deletions of the long arm of theirY chromosome and presenting with azoospermia and with or withoutTurner stigmata. Analysis of their breakpoints by Southern blottingand Y-specific sequence tagged sites (STS) allows us to delimita region located in proximal interval 5 of the Y chromosomeinvolved in skeletal development and growth.     

Multigeneration family with short stature,developmental delay,and dysmorphic features due to 4q27-q28.1 microdeletion

Deletions of the long arm of chromosome 4 are rare but have been previously reported to be associated with craniofacial anomalies, digital anomalies, developmental delay, growth failure, and cardiovascular anomalies [1], [2], [3], [4], [5], [6]. Strehle et al. [1] previously presented 20 patients with 4q deletions and began to construct a phenotype–genotype map for chromosome 4q. This report follows up on that work by providing clinical and molecular cytogenetic data on a three generation pedigree including seven patients with short stature, dysmorphic features, and developmental delay identified to have a 4q27-q28.1 microdeletion of approximately 5.68 Mb by oligonucleotide chromosomal microarray. This family represents a rare report of an inherited interstitial deletion of the long arm of chromosome 4. To our knowledge, only two cases have been previously reported [7], [8]. The contribution of candidate genes in the region is discussed.     

Subtelomeric 6p deletion: clinical, FISH, and array CGH characterization of two cases

Thirty patients have been described with cytogenetically visible deletion of the short arm of chromosome 6. However, subtelomeric 6p deletion detected by subtelomeric specific probes has been reported only twice. We report two new patients with terminal 6p deletion detected by subtelomeric screening using fluorescence in situ hybridization (FISH). The two patients exhibited mental retardation, ocular abnormalities, hearing loss, and a characteristic facial appearance. Detailed FISH analyses with probes covering the distal 6p25 region estimated the size of the terminal deletions to approximately 5.5 Mb and approximately 4.8 Mb. Array-based comparative genomic hybridization (array CGH) was used to confirm the cryptic deletions. Most patients with subtelomeric defects lack a characteristic phenotype. However, some of the subtelomeric deletions result in a specific phenotype, which can direct the clinician towards the diagnosis. Submicroscopic 6p deletion appears to be a recognizable clinical phenotype, and this region should be thoroughly investigated with FISH probes, including at least a subtelomeric 6p probe and a probe covering FOXC1, for patients presenting with a characteristic facial appearance, ocular abnormalities, predominantly anterior-chamber eye defects, hearing loss, and mental retardation.     

Localisation of male determining factors in man: a thorough review of structural anomalies of the Y chromosome.

It is widely accepted that male determination in man depends on the presence of a factor or factors on the Y chromosome. These factors may be localised within the Y chromosome through the study of structural anomalies of the Y. A thorough review of seven different structural anomalies of the Y is presented: dicentric Y chromosomes, Y isochromosomes, ring Y chromosomes, Y; autosome, Y;X, and Y;Y translocations, and Y deletions. The evidence from these studies indicates that a gene or genes on the short arm or the Y near the centromere play a crucial role in the development of the testes. A few studies indicate that one or more factors on the long arm of the Y may also influence testicular development. If such a factor is present on the long arm, then it too must be very near the centromere. The theory that separate genes independently control the initial development and maturation of the tests (on the long and short arms of the Y, respectively) may be premature. Recently proposed arguments in its favour are examined. Some evidence also indicates the presence of a fertility factor on the non-fluorescent segment of the long arm. Relevant information on the H-Y antigen is discussed.     

Constitutional deletion of chromosome 20q in two patients affected with albright hereditary osteodystrophy

Albright hereditary osteodystrophy (AHO) results from heterozygous inactivation of G(s)alpha, encoded by the GNAS1 locus on the distal long arm of chromosome 20. This autosomal dominant condition is characterized by short stature, obesity, shortening of the metacarpals and metatarsals, and variable mental retardation and may also include end-organ resistance to multiple hormones. Small insertions and deletions or point mutations of GNAS1 are found in approximately 80% of patients with AHO. The remainder may be accounted for by larger genomic rearrangements, but none have been reported to date. We now describe two patients with constitutional 20q deletions and features of AHO. Such deletions are rare in the published literature and have not previously been associated with AHO. Molecular genetic analysis confirmed complete deletion of GNAS1 in both patients. Parental origin could be determined in both cases and provides further support for the parent-of-origin effect on the biochemical status of patients with AHO.     

A novel Xp11.22 duplication involving HUWE1 in a male with syndromic intellectual disability and additional neurological findings

Sequence variants and duplications in the HECT, UBA and WWE domain –containing 1 (HUWE1) E3 ubiquitin ligase gene have been associated with X-linked mild to severe intellectual disability (ID), but a solid phenotype pattern among the affected males is still remaining to be established. Here, we report a male patient with sporadic, severe and syndromic ID, carrying a novel and unique 842 kb duplication at Xp11.22, including the dosage-sensitive HUWE1 gene and other fifteen curated RefSeq genes. Expression analysis in the patient and his female relatives confirmed increased HUWE1 mRNA levels, with different X-chromosome inactivation patterns among the female carriers. Our patient differs from those previously described by us and others as he presents encephalomalacia at brain Magnetic Resonance Imaging and diffuse bilaterally and synchronous intercritical irritating paroxysms at electroencephalogram. Overall, our clinical, molecular, and neurological findings sum up the previous data, expanding the phenotype spectrum in Xp11.22 copy gains involving the whole HUWE1 gene in both males and female carriers in light of X-chromosome inactivation patterns.     

Linkage analysis in a large Spanish family with X-linked retinitis pigmentosa: phenotype—genotype correlation

X-linked retinitis pigmentosa (XLRP) accounts for 10–25% of RP families and causes the most severe form of the disease in terms of onset and progression. Although three different loci (RP3, RP2 and RP15) have been proposed on the short arm of the X-chromosome by linkage analysis, RP3 represents the disease locus in the majority of XLRP families.
The identification of female carriers of X-linked RP is important for genetic counselling. The presence of fundus and electroretinogram (ERG) abnormalities have been reported to be as high as 87 and 90%, respectively. However, in clinical practice it has not always been possible to know the carrier state of females at risk.
Thirty-five members of a Spanish family with X-linked RP were evaluated by linkage analysis using nine polymorphic markers (CYBB, DXS1110, M6, DXS6679, DXS1068, DXS1058, MAOA, MAOB and DXS6849) that map to the X-chromosome region Xp21.1 to Xp11.3, in an attempt to determine the carrier state of these females at risk. It was possible to establish that a RP3 mutation is, most likely, segregating in this family.     

Allelic imbalance on chromosome I in human breast cancer. I. Minisatellite and rflp analysis

In order to characterise the role of chromosome I more fully in breast cancer, polymorphic markers mapping along the length of the whole chromosome were used to assess a panel of 71 tumour-lymphocyte pairs for allelic imbalance. Complex patterns of alterations were established that are consistent with cytogenetic data in the literature. Deletion mapping of individuals with loss of heterozygosity identified five independent smallest common regions of deletion, two of which are novel. There are also three discrete regions showing a gain in copy number of one homologue. The two arms of the chromosome may be subject to different events; the short arm primarily undergoes interstitial deletions, whereas the long arm is subject to whole arm events (as both gains and losses) as well as regional deletions.     

Monosomy for the most telomeric, gene-rich region of the short arm of human chromosome 16 causes minimal phenotypic effects

We have examined the phenotypic effects of 21 independent deletions from the fully sequenced and annotated 356 kb telomeric region of the short arm of chromosome 16 (16p13.3). Fifteen genes contained within this region have been highly conserved throughout evolution and encode proteins involved in important housekeeping functions, synthesis of haemoglobin, signalling pathways and critical developmental pathways. Although a priori many of these genes would be considered candidates for critical haploinsufficient genes, none of the deletions within the 356 kb interval cause any discernible phenotype other than alpha thalassaemia whether inherited via the maternal or paternal line. These findings contrast with previous observations on patients with larger (> 1 Mb) deletions from the 16p telomere and therefore address the mechanisms by which monosomy gives rise to human genetic disease.