Familial 14-Mb deletion at 21q11.2-q21.3 and variable phenotypic expression

We report a familial case with a proximal interstitial deletion of chromosome 21q [del(21q)]. Although the mother in the family was phenotypically normal, her first child was affected with both sensorineural hearing loss and moderate mental retardation, and the second affected child had mild mental retardation but not sensorineural hearing loss. We determined breakpoints of the del(21q) in the mother and her two affected children by fluorescence in situ hybridization analysis using 45 DNA clones and the molecular analysis using 21 DNA markers. The proximal breakpoint of the del(21q) was located at a region between 0.33 Mb and 0.46 Mb distal to the centromere, and the distal breakpoint was at a region between 14.6 Mb and 14.9 Mb. The finding indicates that the three individuals had an approximate 14-Mb deletion within 21q11.2-q21.3. Molecular analysis showed that both affected children shared the same maternal haplotype of their del(21q), but a crossover was detected in the paternally inherited normal chromosome 21. These data suggest that unmasking of deleterious genes on the paternally derived chromosome 21 of the two children as a result of the deletion may affect the extent of their mental retardation and/or sensorineural hearing loss. Usher syndrome 1E may be a candidate disease locus related to the sensorineural hearing loss of the first child.     

Familial 14-Mb deletion at 21q11.2–q21.3 and variable phenotypic expression

We report a familial case with a proximal interstitial deletion of chromosome 21q [del(21q)]. Although the mother in the family was phenotypically normal, her first child was affected with both sensorineural hearing loss and moderate mental retardation, and the second affected child had mild mental retardation but not sensorineural hearing loss. We determined breakpoints of the del(21q) in the mother and her two affected children by fluorescence in situ hybridization analysis using 45 DNA clones and the molecular analysis using 21 DNA markers. The proximal breakpoint of the del(21q) was located at a region between 0.33 Mb and 0.46 Mb distal to the centromere, and the distal breakpoint was at a region between 14.6 Mb and 14.9 Mb. The finding indicates that the three individuals had an approximate 14-Mb deletion within 21q11.2–q21.3. Molecular analysis showed that both affected children shared the same maternal haplotype of their del(21q), but a crossover was detected in the paternally inherited normal chromosome 21. These data suggest that unmasking of deleterious genes on the paternally derived chromosome 21 of the two children as a result of the deletion may affect the extent of their mental retardation and/or sensorineural hearing loss. Usher syndrome 1E may be a candidate disease locus related to the sensorineural hearing loss of the first child. Received: March 1, 2002 / Accepted: June 14, 2002     

Mapping susceptibility gene locus for IgA deficiency at del(18)(q22.3-q23); report of familial cryptic chromosome t(18q; 10p) translocations

This study presents a clinical report of the Finnish chromosome t(18q; 10p) translocation family with an overview of eight other selected immunoglobulin A (IgA)-deficient 18q deletion (18q-) patients from seven published articles. The family members show features common to 18q- syndrome such as mental retardation, multiple facial dysmorphism, foot/hand deformities, abnormal myelination of brain white matter, and a spectrum of immunological/infectious disorders including IgA deficiency (IgAD). Genotype-phenotype correlation study of the unbalanced t(18q-; 10p+) translocation family members and other 18q- syndrome reports led to definition of a potential susceptibility gene locus for IgAD at distal region of 18q22.3-q23 between markers D18S812-18qter. The haplo-insufficiency of the 18q22.3-q23 gene region is suggested to be a cause of the IgAD phenotype in 18q- individuals. This 7 Mb IgAD critical region shows significant association with susceptibility region for celiac disease that is frequently connected to IgAD.     

Mosaic microdeletion 18q21 as a cause of mental retardation

We present the clinical and cytogenetic findings in an 8 year old girl with mental retardation, acquired microcephaly, delayed motor skills and stereotypical hand movements. Array comparative genomic hybridization identified a mosaic de novo deletion of approximately 7.505 Mb in chromosome region 18q21.1q21.31, resulting in the loss of one copy of the TCF4 gene as well as 29 other RefSeq genes. The deletion likely occurred early in development as this child has clinical symptoms affecting multiple organ systems, reminiscent of those observed in Pitt–Hopkins syndrome (PHS; OMIM 610954). This case represents the second known example of a mosaic deletion resulting in clinical symptoms consistent with Pitt-Hopkins syndrome, and illustrates the utility of genomic microarray analysis in detecting large mosaic imbalances that may otherwise be missed by G-band analysis.     

Monosomy 18q syndrome and atypical Rett syndrome in a girl with an interstitial deletion (18)(q21.1q22.3)

We describe a 6 1/2-year-old girl with an interstitial deletion of chromosome arm 18q (18q21.1q22.3). Her clinical manifestations are a combination of those found in monosomy 18q syndrome and those of Rett syndrome. Cytogenetic analysis demonstrated a deletion of the long arm of chromosome 18, defined by molecular analysis with polymorphic markers as a de novo interstitial deletion, paternally derived. The findings typical of the 18q- syndrome included mental retardation, midface hypoplasia, and hypoplasia of labia majora, and those typical of Rett syndrome were severe mental retardation, autistic behavior, inappropriate hand-washing movements, epilepsy, attacks of sighing and hyperventilation, and progressive scoliosis since the age of 5 years. She did not have microcephaly, and the mental delay was obvious from an early age without a period of normal development, which makes the diagnosis of Rett syndrome atypical. Previously, a girl with mosaicism for a monosomy 18q associated with Rett syndrome has been described. That girl had a terminal deletion of chromosome 18q, which seems to coincide in part with that in the present girl. It is possible that genes in the distal region of 18q are involved in the etiology of Rett syndrome.     

Magnetic resonance imaging demonstrates incomplete myelination in 18q- syndrome

Magnetic resonance imaging (MRI) and MRI relaxometry were used to investigate disturbed brain myelination in 18q- syndrome, a disorder characterized by mental retardation, dysmorphic features, and growth failure. T1-weighted and dual spin-echo T2-weighted MR images were obtained, and T1 and T2 parametric image maps were created for 20 patients and 12 controls. MRI demonstrated abnormal brain white matter in all patients. White matter T1 and T2 relaxation times were significantly prolonged in patients compared to controls at all ages studied, suggesting incomplete myelination. Chromosome analysis using fluorescence in situ hybridization techniques showed that all patients with abnormal MRI scans and prolonged white matter T1 and T2 relaxation times were missing one copy of the myelin basic protein (MBP) gene. The one patient with normal-appearing white matter and normal white matter T1 and T2 relaxation times possessed two copies of the MBP gene. MRI and molecular genetic data suggest that incomplete cerebral myelination in 18q- is associated with haploinsufficiency of the gene for MBP. Am. J. Med. Genet. 74:422–431, 1997. © 1997 Wiley-Liss, Inc.     

Growth hormone deficiency associated in the 18q deletion syndrome

The 18q- syndrome is one of the commonest deletion syndromes. Clinical characteristics are variable but may include: hypotonia, tapered digits, “carp-like” mouth, mental retardation, and hearing impairment. Growth failure (GF; both weight and height <3%) was reported in 80% of affected individuals. We evaluated growth hormone (GH) sufficiency in 5 18q- syndrome patients, 3 of whom had growth failure (<3% weight and height); the remaining 2 had normal growth parameters. Laboratory evaluation of growth included measurement of IGF-1, IGFBP-3, bone ages and GH response to pituitary provocative agents. Three patients failed to produced adequate GH following stimulation testing. Of 3 patients with inadequate GH production, 1 had normal growth (above 3%). Only 1 of 5 patients had normal GH production and normal growth parameters. Our findings to date suggest that GH deficiency is common in individuals with the 18q- syndrome. The pathogenesis of this finding is unknown. We postulate that a gene(s) on 18q is involved in GH production. Am. J. Med. Genet. 69:7–12, 1997. © 1997 Wiley-Liss, Inc.     

Syndrome of congenital cataracts, sensorineural deafness, Down syndrome-like facial appearance, short stature, and mental retardation: two additional cases

An apparently new syndrome of congenital cataracts, sensorineural deafness, Down syndrome-like facial appearance, short stature, and mental retardation was described by Gripp et al. 1996. The authors reported on two unrelated patients with congenital cataracts, sensorineural deafness, distinctive facial appearance, mental retardation, postnatal short stature, and skeletal changes. We report on two additional patients with findings most similar to the reported patients by Gripp et al. 1996, including bilateral congenital cataracts, hearing loss, craniofacial abnormalities, short stature, skeletal abnormalities, and developmental delay. Both of the patients reported herein had chromosome microarray analysis, which showed normal results in Patient 2 but abnormal results in Patient 1 and his mother who both had a chromosome 11q25 subtelomere deletion. Patient 1 and his mother's findings are atypical for the common findings reported in Jacobsen syndrome (11q terminal deletion syndrome), and consistent with the patients reported by Gripp et al. 1996. The etiology for these cases has been unknown. The microarray results on Patient 1 suggest that the other patients with findings of developmental delay, short stature, congenital cataracts, sensorineural hearing loss, and similar craniofacial features may have either a microdeletion of chromosome 11q terminal region or haploinsufficiency of a gene localized to this region.     

Familial 4.8 MB deletion on 18q23 associated with growth hormone insufficiency and phenotypic variability

The deletion of the long arm of chromosome 18 causes a contiguous gene deletion syndrome with a highly variable phenotype, usually related to the extent of the deleted region. The most commonly reported clinical features include: decreased growth, microcephaly, facial abnormalities, hypotonia, developmental delay, intellectual disability, congenital aural atresia with hearing impairment and limb anomalies. Here we report on a familial terminal deletion of 18q23 region transmitted from a mother to two daughters, resulting in a remarkable phenotypic variability. The deletion was first detected by conventional cytogenetic analysis in one daughter and subsequently characterized using fluorescence in situ hybridization (FISH) and array-CGH. FISH analysis using subtelomeric 18p and 18q probes confirmed the 18qter deletion in the three patients, and FISH with a whole chromosome painting probe specific for chromosome 18 excluded rearrangements with other chromosomes. Array-CGH analysis allowed us to precisely define the extent of the deletion, which spans 4.8?Mb from 71,236,891 to 76,093,303 genomic positions and includes GALR1 and MBP genes, among others. High-resolution analysis of the deletion, besides a detailed clinical assessment, has provided important data for phenotype-genotype correlation and genetic counseling in this family. Furthermore, this study adds valuable information for phenotype-genotype correlation in 18q- syndrome and might facilitate future search for candidate genes involved in each phenotypic trait.     

Deletion involving D15S113 in a mother and son without Angelman syndrome: Refinement of the Angelman syndrome critical deletion region

Deletions of 15q11-q13 typically result in Angelman syndrome when inherited from the mother and Prader-Willi syndrome when inherited from the father. The critical deletion region for Angelman syndrome has recently been restricted by a report of an Angelman syndrome patient with a deletion spanning less than 200 kb around the D15S113 locus. We report here on a mother and son with a deletion of chromosome 15 that includes the D15S113 locus. The son has mild to moderate mental retardation and minor anomalies, while the mother has a borderline intellectual deficit and slightly downslanting palpebral fissures. Neither patient has the seizures, excessive laughter and hand clapping, ataxia or the facial anomalies which are characteristic of Angelman syndrome. The proximal boundary of the deletion in our patients lies between the D15S10 and the D15S113 loci. Our patients do not have Angelman syndrome, despite the deletion of the D15S113 marker. This suggests that the Angelman syndrome critical deletion region is now defined as the overlap between the deletion found in the previously reported Angelman syndrome patient and the region that is intact in our patients. © 1995 Wiley-Liss, Inc.     

Interstitial deletion of chromosome 4, del(4)(q12q21.1), in a mentally retarded boy with a piebald trait,due to maternal insertion,ins(8;4)

A 17-year-old boy who was diagnosed with “Waardenburg syndrome” showed moderate growth and mental retardation. Chromosome analysis showed an apparent interstitial deletion 4q12q21.1. The mother had a direct insertion of the deleted segment into a chromosome 8. The rearrangement was confirmed to be nonreciprocal and an insertion by in situ hybridization using whole chromosome 4 and 8 painting probes. The mother's karyotype is 46,XX,ins(8;4)(q21.2; q12q21.1); that of the propositus is 46,XY, der(4)ins(8;4)(q21.2;q12q21.1)mat. This is the first report of an inherited proximal 4q deletion. Am. J. Med. Genet. 75:78–81, 1998. © 1998 Wiley-Liss, Inc.     

Subtelomeric deletions of 1q43q44 and severe brain impairment associated with delayed myelination

Subtelomeric deletions of 1q44 cause mental retardation, developmental delay and brain anomalies, including abnormalities of the corpus callosum (ACC) and microcephaly in most patients. We report the cases of six patients with 1q44 deletions; two patients with interstitial deletions of 1q44; and four patients with terminal deletions of 1q. One of the patients showed an unbalanced translocation between chromosome 5. All the deletion regions overlapped with previously reported critical regions for ACC, microcephaly and seizures, indicating the recurrent nature of the core phenotypic features of 1q44 deletions. The four patients with terminal deletions of 1q exhibited severe volume loss in the brain as compared with patients who harbored interstitial deletions of 1q44. This indicated that telomeric regions have a role in severe volume loss of the brain. In addition, two patients with terminal deletions of 1q43, beyond the critical region for 1q44 deletion syndrome exhibited delayed myelination. As the deletion regions identified in these patients extended toward centromere, we conclude that the genes responsible for delayed myelination may be located in the neighboring region of 1q43.     

Neurologic manifestations in 18q- syndrome.

We report a mother and son with a deletion at 18q22.3. Both have the typical manifestations of the 18q- syndrome. In addition, both have an action tremor which became apparent in childhood. The mother subsequently developed chorea and dysmetria in late adolescence. Magnetic resonance imaging of their brains showed poor myelination of the central white matter tracts with relatively normal myelination of the corpus callosum. We propose that these neurologic findings are most likely due to a failure of expression of the myelin basic protein gene.     

Patient with del(12)(q12q13.12) manifesting abnormalities compatible with Noonan syndrome

We report on a Japanese boy with interstitial deletion of chromosome 12q12–q13.12, who had multiple congenital anomalies with severe psychomotor retardation. Most of the clinical manifestations were compatible with Noonan syndrome phenotype except for the absence of cardiac defects. Severe mental retardation and intrauterine onset of growth retardation may have been due to the chromosomal deletion. The interstitial deletion does not overlap a putative Noonan syndrome locus, which was recently assigned to 12q22–qter by linkage analysis. Although correlation between the phenotype and del(12)(q12q13.12) was not confirmed, because this is the first report of deletion of proximal 12q, the deleted segment may contain another Noonan syndrome locus. Am. J. Med. Genet. 75:416-418, 1998. © 1998 Wiley-Liss, Inc.     

Beckwith-Wiedemann-like macroglossia and 18q23 haploinsufficiency

Beckwith-Wiedemann syndrome (BWS) is an overgrowth condition with tumor proclivity linked to a genetic imbalance of a complex imprinted region in 11p15.5. A female child with features fitting in with the BWS diagnostic framework and an apparent loss of imprinting (LOI) of the IGF2 gene in 11p15.5 was also reported to have a de novo chromosome 18q segmental deletion (Patient 1), thus pointing at the location of a possible trans-activating regulator element for maintenance of IGF2 imprinting and providing one of the few examples of locus heterogeneity of BWS. A second child with de novo 18q23 deletion and features of macroglossia, naevus flammeus, bilateral inguinal hernia and transient neonatal hypoglycemia, thus also fitting in with the BWS diagnostic framework, is here fully reported (Patient 2). In this child, an analysis of the BWS1 locus precluded any paternal isodisomy and showed a normal imprinting pattern (mono-allelic expression of IGF2 and normal H19 and CDKN1OT1/LIT1 methylation index). In Patients 1 and 2, deletions were shown to overlap, defining a minimal region of haplo-insufficiency of 3.8-5.6 Mb in 18q23. We conclude that this region provides a candidate location for an original macroglossia condition with strong overlap with BWS, but without obvious upstream functional relationship with the BWS1 locus in 11p15.5. Because this minimal region of haplo-insufficiency falls into a common region of deletion in 18q- syndrome, we inferred that this macroglossia condition would follow a recessive pattern of inheritance.     

Translocation 46XY, t (17;18) (q25;q21) in a mentally retarded boy with progressive eye abnormalities

A 10-year-old boy with reciprocal translocation between chromosomes 17 and 18- 46XY,t (17;18) (q25; q21), appeared cytogenetically balanced. The patient was a healthy, thriving boy whose main abnormal feature was moderate mental retardation. However, abnormal ocular signs were present, including macular "fibrosis", optic disc abnormalities with a traction retinal detachment, tapeto-retinal degeneration, and tilting of the disc to the nasal side. These changes are consistent with the ocular changes previously described in the 18q- syndrome, suggesting that there has been a minimal deletion of chromosome material at the 18q21 breakpoint. The case also demonstrates that the ocular changes of the 18- syndrome may be progressive.     

The association of Angelman''s syndrome with deletions within 15q11-13.

The inheritance of Angelman's syndrome, a disorder characterised by mental retardation, epilepsy, ataxia, and a happy disposition, is debated because affected sibs occur less frequently than expected with autosomal recessive inheritance. After discovering two unrelated patients with a small deletion of the proximal long arm of chromosome 15, 10 further patients with Angelman's syndrome were reassessed. Five had apparently normal karyotypes, four had a deletion within 15q11-13, and one had a pericentric inversion, inv(15)(p11q13) involving the same chromosomal region. In the latter case, the healthy mother had the same pericentric inversion, indicating that the patient also had a submicroscopic mutation on his other chromosome 15. These data map the Angelman locus to 15q11-13 and suggest that de novo visible deletions (associated with a low recurrence risk) and autosomal recessively inherited cases combine to give an overall sib recurrence risk of less than 25%.     

Two new cases with microdeletion of 17q23.2 suggest presence of a candidate gene for sensorineural hearing loss within this region

Microdeletion of the 17q23.2 region has very recently been suggested as a new emerging syndrome based on the finding of 8 cases with common phenotypes including mild-to-moderate developmental delay, heart defects, microcephaly, postnatal growth retardation, and hand, foot, and limb abnormalities. In this report, we describe two new 17q23.2 deletion patients with mild intellectual disability and sensorineural hearing loss. They both had submicroscopic deletions smaller than the common deleted region for the 8 previously described 17q23.2 microdeletion cases. TBX4 was previously suggested as the responsible gene for the heart or limb defects observed in 17q23.2 deletion patients, but the present cases do not have these features despite deletion of this gene. The finding of sensorineural hearing loss in 5 of the 10 cases, including the present cases, with a microdeletion at17q23.2, strongly suggests the presence of a candidate gene for hearing loss within this region. We screened 41 patients with profound sensorineural hearing loss for mutations of TBX2 and detected no mutations.     

Neurologic manifestations in 18q– syndrome

We report a mother and son with a deletion at 18q22.3. Both have the typical manifestations of the 18q– syndrome. In addition, both have an action tremor which became apparent in childhood. The mother subsequently developed chorea and dysmetria in late adolescence. Magnetic resonance imaging of their brains showed poor myelination of the central white matter tracts with relatively normal myelination of the corpus callosum. We propose that these neurologic findings are most likely due to a failure of expression of the myelin basic protein gene.     

Deletion mapping of the β-glucuronidase gene

GUSB, the gene for β-glucuronidase, has been localized to the proximal long arm of chromosome 7 between 7q11.2 and 7q22. Deficiency of β-glucuronidase results in mucopolysaccharidosis type VII (MPS VII, Sly syndrome). The enzymatic defect has been demonstrated in cultured skin fibroblasts, leukocytes and serum of affected patients. An 8-yr-old boy presented with manifestations similar to MPS VII (mental retardation, short stature, “coarse” facial appearance, mild skeletal involvement and recurrent lower respiratory tract infection) but other, discrepant abnormalities, e. g., bilateral iris colobomata and cleft palate. Normal activity of β-glucuronidase was found in the patient's leukocytes. Chromosome analysis disclosed an interstitial deletion of 7q with one breakpoint at the interface between bands 11.22 and 11.23 and the other breakpoint within band 21.1. DNA from this patient's leukocytes was analyzed for dosage of GUSB sequences. This locus appeared to be present at the normal diploid level. These findings suggest that GUSB is not in the portion of chromosome 7 deleted in our case, narrowing the smallest region of overlap to 7q21.1 → 7q22. We therefore assign the β-glucuronidase gene to 7q21.1 → 7q22.