De novo subtelomeric deletion of 15q associated with satellite translocation in a child with developmental delay and severe growth retardation

We report on a case of satellited 15q with subtelomeric deletion in a girl with delayed development and severe growth retardation. The patient also has a triangular face, downturned angles of the mouth, micrognathia, and minor limb malformations including mild talipes equinovarus, genu recurvatum, and increased dorsiflexion of both limbs. Cytogenetic analysis using standard GTG banding showed a female karyotype with a satellited-like structure at the distal long arm of one chromosome 15. Silver staining of the nucleolar organizing region (AgNOR) confirmed the presence of a satellite DNA translocation at the lesion. Analysis using fluorescent in situ hybridization (FISH) detected a subtelomeric deletion of the terminal 15q. Additional molecular analysis using microsatellite markers along the long arm of chromosome 15 defined a maximally deleted region at approximately 4.7 Mb. Haploinsufficiency of the IGF1R gene expression is thought to be the cause of growth delay in all 15q terminal deletion including our patient.     

A de novo deletion of 20q11.2-q12 in a boy presenting with abnormal hands and feet, retinal dysplasia, and intractable feeding difficulty

Proximal interstitial deletions involving 20q11-q12 are very rare. Only two cases have been reported. We describe another patient with 20q11.21-q12 deletion. We precisely mapped the 6.5-Mb deletion and successfully determined the deletion landmarks at the nucleotide level. Common clinical features among the three cases include developmental delay, intractable feeding difficulties with gastroesophageal reflux, and facial dysmorphism including triangular face, hypertelorism, and hypoplastic alae nasi, indicating that the 20q11.2-q12 deletion can be a clinically recognizable syndrome. This is also supported by the fact that the three deletions overlap significantly. In addition, unique features such as arthrogryposis/fetal akinesia (hypokinesia) deformation and retinal dysplasia are recognized in the patient reported herein.     

Submicroscopic Xpter deletion in a boy with growth and mental retardation caused by a familial t(X;14)

In a 3-year-old boy with short stature, developmental delay, and dry skin, steroid sulphatase deficiency and a submicroscopic terminal deletion of Xp were found. Except for the short stature, no major clinical signs of X-linked recessive chondrodysplasia punctata could be observed. His mother had lowered steroid sulphatase activity compatible with carriership for X-linked ichthyosis and a submicroscopic translocation (X;14)(p22.31;p11.1). This finding combined with a normal amplification of exons 1, 5, and 10 of the STS gene from propositus' DNA suggested a breakpoint upstream of the STS gene. The submicroscopic maternal translocation had important implications for genetic counseling. This case report illustrates that contiguous gene syndrome related to the Xpter region may have an atypical clinical presentation and the usefulness of combined clinical, biochemical, molecular, and fluorescence in situ hybridization analysis. Am. J. Med. Genet. 87:189–194, 1999. © 1999 Wiley-Liss, Inc.     

Age at menarche and comparison of the growth and performance of pre- and post-menarcheal girls in China

The median menarcheal ages (MMAs) of Chinese girls in 1991 were calculated by using the status quo method and probit analysis in 64,322 schoolgirls 8–18 years of age. The sample was randomly selected from 29 provinces of China. The MMAs were 13.01 ± 1.19 and 13.64 ± 1.24 years for urban and rural girls, respectively. These estimates were 0.16 and 0.20 years lower than that of Chinese urban and rural girls in 1985, respectively. The associations between growth status and the timing of menarche were also analyzed by comparing of 10 indicators of somatic growth and motor ability between the pre- and post-menarcheal girls. Early maturers consistently have high means of stature, weight, and vital capacity than late maturers. By contrast, the late maturers tend to have a linear physique and more potential of increasing stature and lower limbs into late adolescence. Late maturers also tend to have more potential in catching up in motor abilities, which were inferior to those of early maturers during early adolescence. Am. J. Hum. Biol. 9:205–212, 1997. © 1997 Wiley-Liss, Inc.     

Chromosomal microarray analysis (CMA) detects a large X chromosome deletion including FMR1, FMR2, and IDS in a female patient with mental retardation

Chromosomal microarray analysis (CMA) by array-based comparative genomic hybridization (CGH) is a new clinical test for the detection of well-characterized genomic disorders caused by chromosomal deletions and duplications that result in gene copy number variation (CNV). This powerful assay detects an abnormality in approximately 7-9% of patients with various clinical phenotypes, including mental retardation. We report here on the results found in a 6-year-old girl with mildly dysmorphic facies, obesity, and marked developmental delay. CMA was requested and showed a heterozygous loss in copy number with clones derived from the genomic region cytogenetically defined as Xq27.3-Xq28. This loss was not cytogenetically visible but was seen on FISH analysis with clones from the region. Further studies confirmed a loss of one copy each of the FMR1, FMR2, and IDS genes (which are mutated in Fragile X syndrome, FRAXE syndrome, and Hunter syndrome, respectively). Skewed X-inactivation has been previously reported in girls with deletions in this region and can lead to a combined Fragile X/Hunter syndrome phenotype in affected females. X-inactivation and iduronate 2-sulfatase (IDS) enzyme activity were therefore examined. X-inactivation was found to be random in the child's peripheral leukocytes, and IDS enzyme activity was approximately half of the normal value. This case demonstrates the utility of CMA both for detecting a submicroscopic chromosomal deletion and for suggesting further testing that could possibly lead to therapeutic options for patients with developmental delay.     

Paternal deletion from Snrpn to Ube3a in the mouse causes hypotonia, growth retardation and partial lethality and provides evidence for a gene contributing to Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is caused by paternal deficiency of human chromosome 15q11-q13. There is conflicting evidence from human translocations regarding the direct involvement of SNRPN in the pathogenesis of PWS and it is not known if the phenotypic features result from the loss of expression of a single imprinted gene or multiple genes. In an attempt to dissect genotype/phenotype correlations for the homologous region of mouse chromosome 7C, we prepared three mutant genotypes: (i) mice with a deletion of Snrpn exon 2, which removes a portion of a small, upstream open reading frame (ORF); (ii) mice with double targeting for Snrpn exon 2 and Ube3a; (iii) mice deleted from Snrpn to Ube3a, removing coding exons for both loci and intervening genes. Mice deleted for Snrpn exon 2 have no obvious phenotypic abnormalities and switching of the genomic imprint for the region is conserved. Mice carrying the Snrpn - Ube3a deletion on the paternal chromosome showed severe growth retardation, hypotonia and approximately 80% lethality before weaning. The surviving mice were fertile and were not obese up to 14 months of age. The deletion was transmitted for multiple generations and continued to cause partial lethality when inherited paternally, but not when inherited maternally. The normal imprinted expression and methylation patterns of necdin, a gene outside the deletion region, indicate that the deletion is not an imprinting mutation. The data suggest the presence of a paternally expressed structural gene between Snrpn and Ipw whose deficiency causes lethality, although other possibilities exist, including position effects on expression of imprinted genes or that simultaneous deficiency of both ORFs of Snrpn causes lethality.     

Submicroscopic Xpter deletion in a boy with growth and mental retardation caused by a familial t(X;14).

In a 3-year-old boy with short stature, developmental delay, and dry skin, steroid sulphatase deficiency and a submicroscopic terminal deletion of Xp were found. Except for the short stature, no major clinical signs of X-linked recessive chondrodysplasia punctata could be observed. His mother had lowered steroid sulphatase activity compatible with carriership for X-linked ichthyosis and a submicroscopic translocation (X;14)(p22.31;p11.1). This finding combined with a normal amplification of exons 1, 5, and 10 of the STS gene from propositus' DNA suggested a breakpoint upstream of the STS gene. The submicroscopic maternal translocation had important implications for genetic counseling. This case report illustrates that contiguous gene syndrome related to the Xpter region may have an atypical clinical presentation and the usefulness of combined clinical, biochemical, molecular, and fluorescence in situ hybridization analysis.     

Mental retardation in a girl with a subtelomeric deletion on chromosome 20q and complete deletion of the myelin transcription factor 1 gene (MYT1)

A great number of syndromes and inborn errors of metabolism associated with impaired development have been observed, but the aetiology of mental retardation remains unclear in a considerable proportion of cases. Here, we present the clinical and molecular data from a patient with a new de novo subtelomeric deletion on chromosome 20 [46,XX.ish del(20)(qter-)]. For further refinement, bacterial artificial chromosome clones are used. The deletion spans exactly two genes called MYT1 and PCMTD2 . Both genes play an important role in myelination and regulating neural differentiation. Loss of these two genes seems to be responsible for the severe mental retardation and mild facial dysmorphic features in our young patient. It might show the phenotypic picture of this specified deletion.     

A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation

X-linked mental retardation has been traditionally divided into syndromic (S-XLMR) and non-syndromic forms (NS-XLMR), although the borderlines between these phenotypes begin to vanish and mutations in a single gene, for example PQBP1, can cause S-XLMR as well as NS-XLMR. Here, we report two maternal cousins with an apparently X-linked phenotype of mental retardation (MR), microphthalmia, choroid coloboma, microcephaly, renal hypoplasia, and spastic paraplegia. By multipoint linkage analysis with markers spanning the entire X-chromosome we mapped the disease locus to a 28-Mb interval between Xp11.4 and Xq12, including the BCOR gene. A missense mutation in BCOR was described in a family with Lenz microphthalmia syndrome, a phenotype showing substantial overlapping features with that described in the two cousins. However, no mutation in the BCOR gene was found in both patients. Subsequent mutation analysis of PQBP1, located within the delineated linkage interval in Xp11.23, revealed a 2-bp deletion, c.461_462delAG, that cosegregated with the disease. Notably, the same mutation is associated with the Hamel cerebropalatocardiac syndrome, another form of S-XLMR. Haplotype analysis suggests a germline mosaicism of the 2-bp deletion in the maternal grandmother of both affected individuals. In summary, our findings demonstrate for the first time that mutations in PQBP1 are associated with an S-XLMR phenotype including microphthalmia, thereby further extending the clinical spectrum of phenotypes associated with PQBP1 mutations.     

Interstitial deletion in 3q in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and microcephaly, mild mental retardation and growth delay: clinical report and review of the literature

We present a boy with blepharophimosis, ptosis, epicanthus inversus, microcephaly, mild mental retardation, and growth delay. Chromosomal analysis revealed a male karyotype with an interstitial deletion in the long arm of chromosome 3. DNA-analysis showed that the deletion is of maternal origin and encompasses the region between markers D3S1535 and D3S1593. The deletion contains not only the FOXL2 gene, but also the gene encoding ataxia-telangiectasia and Rad3-related protein (ATR). Mutations in FOXL2 have been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). ATR has been identified as a candidate gene for Seckel syndrome, an autosomal recessive syndrome that comprises growth retardation, microcephaly, and mental retardation. We hypothesize that our patient has a contiguous gene syndrome and that the non-BPES-associated abnormalities (microcephaly, mild mental retardation, and growth delay) are the result of the deletion of the maternal ATR gene. However, it has not yet been excluded that haploinsufficiency of some other gene in this region plays a role.     

New case of interstitial deletion 12(q15-q21.2) in a girl with facial dysmorphism and mental retardation

Interstitial deletions of the long arm of chromosome 12 are rare rearrangements with only 15 cases reported in the literature. The phenotype may include facial dysmorphism, developmental delay, ectodermal abnormalities, cardiac and renal malformations depending on breakpoints' position. Here, we describe a third case of 12(q15-q21.2) deletion ascertained through CGH-array analyses and provide a 5-year follow-up. The patient presented with pre- and postnatal growth retardation, congenital heart defect, developmental delay, and facial dysmorphism changing with age, underlining the importance of long-term follow-up. We compared this new case with previous observations of 12q deletions in order to propose phenotype-karyotype correlations.     

A 15-bp deletion in exon 5 of the ornithine aminotransferase (OAT) locus associated with gyrate atrophy.

Gyrate atrophy of the choroid and retina (GA) is an autosomal recessive disorder in which a deficiency of the mitochondrial matrix enzyme ornithine aminotransferase (OAT) leads to progressive blindness. Previously, we and others have reported a number of missense mutations and splice defects in the OAT gene associated with GA. In the present case, through sequencing of the PCR amplified cDNA products, we have detected a novel 15-bp deletion within exon 5 of the OAT gene which retains the original reading frame. The deleted PCR product is the only one produced from the patient's mRNA, while mRNA from the patient's mother yields both deleted and normal length PCR products. The alternate, apparently nonexpressing OAT allele in this patient was inherited from the father, who displays only the normal length PCR product. The codon at the deletion joint remains unaltered, predicting the loss of the pentapeptide Tyr-Thr-Val-Lys-Gly without any other amino acid change. The breakpoints are adjacent to or within two copies of a 4-bp direct repeat, which may have implications for the mechanism of deletion.     

The syndrome of retinal pigmentary degeneration, microcephaly, and severe mental retardation (Mirhosseini-Holmes-Walton syndrome): report of two patients

We report on two daughters, born to consanguineous parents, who had severe mental retardation, microcephaly, retinal pigmentary degeneration, and spastic cerebral palsy. We think that this syndrome is the same as that described by Mirhosseini et al [1972] (McK-26805). The presence of consanguinity favors the hypothesis of autosomal recessive inheritance.     

A male infant with a 9.6 Mb terminal Xp deletion including the OA1 locus: Limit of viability of Xp deletions in males

Males with deletions of or within Xp22.3-pter display variable contiguous gene syndromes including manifestations of Léri-Weill syndrome, chondrodysplasia punctata, mental retardation, ichthyosis, Kallmann syndrome, and ocular albinism. Herein, we report on a male infant with a large, cytogenetically visible, terminal Xp deletion defined by extensive FISH and STS marker analysis to encompass 9.6 Mb, and findings of all of the disorders mentioned above. His deletion approximates the largest Xp terminal deletion ever reported in a male individual. Since the extent of terminal Xp deletions viable in males is limited by the position of male lethal genes in Xp22.2 at about 10-11 Mb from the telomere, this patient falls into the category of the most severe male terminal Xp deletion phenotype.     

Heterozygous deletion at 14q22.1-q22.3 including the BMP4 gene in a patient with psychomotor retardation, congenital corneal opacity and feet polysyndactyly

Here we report on a 1-year-old Japanese girl with psychomotor retardation, bilateral congenital corneal opacity and bilateral postaxial polysyndactyly of the feet. Although she had a normal female karyotype, our in-house bacterial artificial chromosome (BAC)-based array-CGH analysis successfully detected at least a 2.7-Mb heterozygous deletion at 14q22.1-q22.3 harboring 18 protein-coding genes. Among the genes, BMP4 was a candidate for the gene causing the abnormalities of both the eye and digits. It was previously reported that the BMP family was correlated with the morphogenesis of digits and ocular development, and Bmp4 heterozygous null mice revealed skeletal abnormalities including polydactyly and ocular anterior segment abnormalities. Patients with a deletion including BMP4 also hadabnormalities of the eye and digits. These previous reports support that a haplo-insufficiency of the BMP4 gene likely caused the congenital ocular and digit abnormalities. Moreover, among the other genes contained in the deletion, GMFB is a candidate for the gene responsible for the psychomotor retardation.     

Fluorescent in situ hybridisation (FISH) for hemizygous deletion at the elastin locus in patients with isolated supravalvular aortic stenosis.

Both Williams syndrome and isolated supravalvular aortic stenosis (SVAS) are caused by mutations at the elastin locus. Deletion demonstrable by FISH is the hallmark of Williams syndrome, whereas the mutations reported so far in SVAS have been more subtle. FISH positive elastin hemizygosity has not been reported in isolated SVAS. This report records our experience of FISH for elastin deletion in isolated SVAS and specifically reports a patient with non-Williams related SVAS, positive for the elastin deletion by FISH.