Pericentric inversion with partial 7(q35-->qter) duplication and 7pter deletion: diagnosis by cytogenetic and fish analysis in a 29-year-old male patient

We report on a 29-year-old male patient with an inverted 7(q35-qter) duplication diagnosed by combining cytogenetic and FISH studies. Traditional G-banding detected an abnormally long chromosome 7 which was further demonstrated to be entirely of chromosome 7 origin by using fluorescent whole chromosome 7 painting. The presence within the additional segment of a signal for 7q36 region (Williams control probe) and the absence of signals for 7q33 (Y938G5 probe) and 7q34 (Y815G5 probe) regions indicated that the breakpoint for this rearrangement was distal to 7q34 and proximal to 7q36. A distal 7p22 deletion was confirmed by the absence of signal for the 7p subtelomeric probe. Apart from kyphosis, developmental/mental retardation and abnormal ears, the clinical features of the present patient, who is the oldest individual ever reported with this duplication/deletion, were not typical for partial 7q trisomy syndrome. A review of the cases reported with 7(q35-qter) duplication is made and shows important clinical variability but constantly normal pre- and postnatal growth, a feature which can therefore be confirmed as distinctive of distal 7q trisomy syndrome.     

A case with de novo interstitial deletion of chromosome 7q21.1-q22

A case with de novo interstitial deletion of chromosome 7q21.1-q22: A patient with multiple congenital anomalies was found to have a de novo proximal interstitial deletion of chromosome 7q21.1-q22. The patient was 10.5 years of age, and manifestations include growth retardation (below 3rd percentile), mental retardation, mild microcephaly, hypersensitivity to noise, mild spasticity, short palpebral fissures, alternant exotropia, compensated hypermetropic astigmatism, hypotelorism, hypoplastic labia majora and minora, clinodactyly of fingers 4 and 5. Molecular studies revealed that the deletion had a paternal origin, while chromosomes of both parents cytogenetically were shown to be normal. Molecular, and fluorescence in situ hybridization (FISH) analyses confirmed no deletion at the Williams-Beuren Syndrome region. Some of the heterogeneous clinical findings were consistent with previously reported cases of same chromosomal breakpoints.     

Molecular characterization of patients with 18q23 deletions.

The 18q- syndrome is a deletion syndrome that is characterized by mental retardation, hearing loss, midfacial hypoplasia, growth deficiency, and limb anomalies. Most patients with this syndrome have deletions from 18q21-qter. We report on three patients with deletions of 18q23. A mother and daughter with identical deletions of 18q23 have many of the typical features of the 18q- syndrome, including midfacial hypoplasia and hearing loss. In contrast, the third patient has few of the symptoms of the 18q- syndrome. A contig of the 18q23 region was generated to aid in the mapping of the breakpoints. FISH was used to map both breakpoints to the same YAC clone. Furthermore, somatic-cell hybrids from the daughter and the third patient were isolated. The mapping results of sequence-tagged sites relative to the two breakpoints were identical, suggesting that the two deletion breakpoints map very close to one another. The analyses of these patients demonstrate that the critical region for the 18q- syndrome maps to 18q23 but that a deletion of 18q23 does not always lead to the clinical features associated with the syndrome. These patients demonstrate the wide phenotypic variability associated with deletions of 18q.     

Interstitial "de novo" tandem duplication of 7(q31.1-q35): first reported case

A patient carrying a de novo 7q31-35 duplication is presented. The tandem duplication was confirmed by FISH analysis. The case seems to be the first in the literature and, in spite of the large size of the duplicated region, he shows mild facial dysmorphism and a moderate mental retardation. The clinical findings of the dup7q published cases are compared in order to define a possible common phenotype.     

Spectral karyotyping and fluorescence in situ hybridization analysis of de novo partial trisomy 7p (7p21.2-->pter) and partial monosomy 12q (12q24.33-->qter)

An 8-year-old boy presenting with hypotonia, moderate mental retardation, developmental delay, and psychomotor retardation is reported. Magnetic resonance imaging of the brain at age 3 years revealed a Dandy-Walker variant. Cytogenetic analysis of the peripheral blood revealed a derivative chromosome 12 with unknown additional material attached to the distal region of the long arm of chromosome 12. The parental karyotypes were normal. Spectral karyotyping (SKY) using the 24-color SKY probes and fluorescence in situ hybridization (FISH) using the specific 7p, 7q, 12p, and 12q telomeric probes confirmed a duplication of distal 7p and a deletion of terminal 12q. The karyotype of the proband was designated as 46,XY.ish der(12)t(7;12) (p21.2;q24. 33)(SKY+, 7pTEL+, 12qTEL-). The present case provides evidence for the association of partial trisomy 7p (7p21.2-->pter) and partial monosomy 12q (12q24.33-->qter) with a cerebellar malformation and the usefulness of SKY and FISH in the identification of a de novo aberrant chromosome resulting from an unbalanced translocation.     

Boy with seizures (West syndrome) and distal 7q duplication syndrome due to an unbalanced 7q;9p translocation

We report a 15 month old boy with prominent metopic suture, epicanthal folds, strabismus, low-set ears, microretrognathia, large anterior fontanel, bilateral simian creases, muscular hypotonia, and severe psychomotor retardation. He also had West syndrome. An electroencephalogram showed hypsarrythmia, and cranial MR indicated a myelinisation delay. Standard karyotyping showed additional material on one chromosome 9p. Using FISH, a terminal 7q duplication spanning 26 Mb in size and a terminal 9p deletion sized (at least) 9.1 Mb were identified. The father had a karyotype of t(7;9)(q33;p23) and the mother's karyotype was normal. The boy presented typical facial features of the distal 7q duplication syndrome but no genital anomalies attributable to his distal 9p deletion. We assume that the severe epilepsy is likely due to the trisomy 7q.     

Identification of a yeast artificial chromosome clone spanning a translocation breakpoint at 7q32.1 in a Smith-Lemli-Opitz syndrome patient.

Smith-Lemli-Opitz syndrome (SLOS) is a mental retardation/multiple congenital anomaly syndrome. The gene(s) involved has not been mapped or cloned, but, recently, a biochemical abnormality in cholesterol biosynthesis has been shown to occur in most SLOS patients. The defect is suspected to occur in the penultimate step of the cholesterol pathway, involving the enzyme 7-dehydrocholesterol reductase, which has not been isolated. On the basis of the hypothesis that a de novo balanced translocation [t(7;20)(q32.1;q13.2)] in an SLOS patient directly interrupts the SLOS gene, positional cloning techniques are being employed to localize and identify the SLOS gene. We report the identification of a chromosome 7-specific YAC that spans the translocation breakpoint, as detected by FISH. This is the first study narrowing a candidate SLOS region and placing it on physical and genetic maps of the human genome.     

Small terminal 10q26 deletion in a male patient with Noonan-like stigmata: diagnosis by cytogenetic and FISH analysis

A male patient is reported with terminal 10q26 deletion, developmental retardation, special behaviour, and multiple clinical anomalies including hypotonia, short stature of postnatal onset, short webbed neck, craniofacial dysmorphism, pectus excavatum with widely spaced small nipples, cryptorchidism with scrotal hypoplasia, limb and musculoskeletal anomalies. The facial dysmorphism mainly consisted of trigonocephaly, a long, triangular and asymmetrical face, hypertelorism with pseudoepicanthus, broad nasal bridge, high-arched palate, retrognathia, low-set dysplastic auricles and, on ophthalmologic examination, strabismus, astigmatism and myopia. Some of these clinical stigmata were suggesting the diagnosis of Noonan syndrome. The extremities showed special features including shortening of proximal limbs, brachydactyly with syndactyly of toes II-III and left fingers III-IV, hypoplastic toenails and joint abnormalities. A diastasis of abdominal muscles was noted and, on X-rays a thoracic scoliosis and bilateral coxa valga were evidenced. Analyses of G- and T-banded chromosomes complemented by FISH analyses using different subtelomere probes detected a terminal 10q26 deletion. Subsequent FISH studies using different probes of the 10q26 region were performed in an attempt to closely define the breakpoint and the extent of the deletion and, thereby, to allow karyotype/phenotype comparison between this patient and a previously reported case with an apparently similar 10q26 deletion.     

Isolation of the human chromosome 22q telomere and its application to detection of cryptic chromosomal abnormalities

A number of human telomeres have been successfully cloned using a modified yeast artificial chromosome (YAC) vector (half-YAC) cloning strategy, but to date, human chromosome 22q has not been identified by this approach. We used an alternative approach of genomic walking, starting from a subtelomeric sequence, TelBam3.4, present on a number of human chromosomes including 22q. This approach was successful in the development of a cosmid contig representing the terminal 140 kb of human chromosome 22q, providing telomeric closure of the genetic and physical maps for 22q. The most distal region of the contig contains subtelomeric repeats which crosshybridize to a number of chromosomes, while the proximal sequences are unique for 22q. The unique sequence cosmid was used as a 22qter-specific probe for fluorescence in situ hybridization (FISH) analysis, which confirmed that this cosmid was distal to the most telomeric marker previously available for chromosome 22. In addition, this cosmid was used to document a 22q terminal deletion that was not detectable by conventional cytogenetic analysis. Unique telomere-specific FISH probes such as this one will have significant diagnostic value in the detection of cryptic deletions and translocations in patients with unexplained mental retardation and other patient populations. Received: 21 November 1995     

FISH-mapping of a 100-kb terminal 22q13 deletion

Both cytogenetically visible and cryptic deletions of the terminal region of chromosome 22q are associated with a clinical phenotype including mental retardation, delay in expressive speech development, hypotonia, normal to accelerated growth and minor facial dysmorphic features. The genes responsible for the development of the phenotype have not yet been identified, but a distal localization is probable, since the cytogenetically visible and the cryptic deletions show a similar pattern of symptoms. We report a 33-year-old woman with a submicroscopic 22q13 deletion, mild mental retardation, speech delay, autistic symptoms and mild facial dysmorphic features. The deletion was mapped by FISH using cosmid probes from terminal 22q13, and the size of the deletion was estimated to be 100 kb. Three genes are affected by the deletion in this patient. ACR and RABL2B are deleted and proSAP2 is disrupted. This observation, together with recently published data, supports the notion that proSAP2 is the most important contributor to the 22q13 deletion phenotype.     

An adult patient with a distal interstitial 14q deletion: clinical report and literature review

We report a patient with an interstitial 14q32.1-->q32.3 deletion and review the literature. The adult patient presented with moderate mental retardation, a friendly behavior and a non-specific phenotype. The deletion seemed to be terminal but with FISH probes appeared to be interstitial. Comparison with other 14q terminal and interstitial deletion patients reported in literature and those with a ring 14 chromosome is given.     

Duplication dup(1)(q41q44) defined by fluorescence in situ hybridization: delineation of the 'trisomy 1q42-->qter syndrome'

We report on a novel case of pure partial tandem duplication 1q42q43 confirmed by fluorescence in situ hybridization (FISH). We compare the manifestations of our patient with similar cases previously reported. We conclude that the most common clinical manifestations of trisomy 1q42qter are prenatal and postnatal growth retardation, relative macrocephaly, triangular face, prominent forehead, broad nasal bridge, abnormal philtrum, micro/retrognathia, cardiac defects and mental retardation. We would like to emphasize the importance of the FISH technique in the identification of the duplicated segment.     

18q部分单体患儿的细胞和分子遗传学研究

临床发现1例智力低下伴轻度发育迟缓的女性患儿,对患儿进行G显带高分辨染色体核型分析, 发现18q21→qter缺失, 经多色荧光原位杂交和双色荧光原位杂交证实, 确定其核型为46,XX,del(18)(pter→q21:),ish del(18)(D18Z1+, qter-)。用DNA多态性方法分析, 该患儿从18q22.1至18qter区域内至少有8.7 Mbp丢失, 有MBP基因和GALNR基因缺失。缺失的18号染色体源自父亲。患者的智力低下和生长发育迟缓是18q21→qter缺失的结果, 或许与MBP基因和GALNR基因的缺失有关。     

Maternal balanced translocation (4;21) leading to an offspring with partial duplication of 4q and 21q without phenotypic manifestations of Down syndrome

We describe an 8-years old female with supernumerary chromosome der(21)t(4;21)(q25;q22) resulting in partial trisomy 4q25-qter and partial trisomy 21(pter-q22). The extra material was originated from a reciprocal balanced translocation carrier mother (4q;21q). Karyotyping was confirmed by FISH using whole chromosome painting probes for 4 and 21q and using 21q22.13-q22.2 specific probe to rule out trisomy of Down syndrome critical region. Phenotypic and cytogenetic findings were compared with previously published cases of partial trisomy 4q and 21q. Our patient had the major criteria of distal trisomy 4q namely severe psychomotor retardation, growth retardation, microcephaly, hearing impairment, specific facies (broad nasal root, hypertelorism, ptosis, narrow palpebral fissures, long eye lashes, long philtrum, carp like mouth and malformed ears) and thumbs and minor feet anomalies. In spite of detection of most of the 3 copies of chromosome 21, specific features of Down syndrome (DS) were lacked in this patient, except for notable bilateral symmetrical calcification of basal ganglia. This report represents further delineation of the phenotype-genotype correlation of trisomy 4q syndrome. It also supports that DS phenotype is closely linked to 21q22. Nevertheless, presence of basal ganglia calcification in this patient may point out to a more proximal region contributing in its development in DS, or that genes outside the critical region may influence or control manifestations of DS features.     

8q12.1q12.3 de novo microdeletion involving the CHD7 gene in a patient without the major features of CHARGE syndrome: Case report and critical review of the literature

CHARGE syndrome is an autosomal dominant inherited disorder characterized by a specific and recognizable pattern of anomalies. De novo mutations or deletions of the gene encoding chromodomain helicase DNA binding protein 7 (CHD7) are the major cause of CHARGE syndrome. In this report, we describe a patient with a typical phenotype characterized by psychomotor retardation, hypertrichosis, facial asymmetry, synophria, failure to thrive, developmental delay and gastro-esophageal reflux, carrying a de novo 6.04 Mb interstitial deletion in 8q12.1q12.3 detected by single nucleotide polymorphism (SNP) array analysis. Despite the deletion includes CHD7 and although the patient shares some of the clinical features of the CHARGE syndrome, she does not fulfill the clinical criteria for this syndrome. To the best of our knowledge, this is the second case with an entire deletion of the CHD7 gene not leading to CHARGE syndrome and, for this reason, useful to expand and further delineate the clinical features associated with the 8q12.1q12.3 deletion. Furthermore, the literature review revealed that the phenotype secondary to duplications of the same region partially overlaps with the phenotype reported in this study. Selected genes that are present in the hemizygous state and which might be important for the phenotype of this patient, are discussed in context of the clinical features.     

Brachydactyly and Mental Retardation: An Albright Hereditary Osteodystrophy–like Syndrome Localized to 2q37

We report five patients with a combination of brachymetaphalangia and mental retardation, similar to that observed in Albright hereditary osteodystrophy (AHO). Four patients had cytogenetically visible de novo deletions of chromosome 2q37. The fifth patient was cytogenetically normal and had normal bioactivity of the α subunit of Gs (Gsα), the protein that is defective in AHO. In this patient, we have used a combination of highly polymorphic molecular markers and FISH to demonstrate a microdeletion at 2q37. The common region of deletion overlap involves the most telomeric 2q marker, D2S125, and extends proximally for a maximum distance of 17.6 cM. We suggest this represents a consistent phenotype associated with some deletions at 2q37 and that genes important for skeletal and neurodevelopment lie within this region. Screening for deletions at this locus should be considered in individuals with brachymetaphalangia and mental retardation. Furthermore, 2q37 represents a candidate region for type E brachydactyly.     

Characterization of an interstitial deletion del(13)(q22q32) using microdissection and sequential FISH and G-banding

The objective of this study was to delineate a chromosome 13 abnormality and establish its clinical correlation by using molecular cytogenetics procedures. A newborn boy presented with clinical findings, including mild symmetric intrauterine growth retardation (IUGR), small ears with thickened helices, a scalp lesion, short fifth fingers, missing toes, and talipes equinovarus. Routine G-banding of cultured peripheral blood cells revealed that the patient had one abnormal and shortened chromosome 13, but uncertainty remained as to whether the abnormality was the result of an interstitial deletion or a translocation. Thirteen copies of G-banded abnormal chromosomes 13 were isolated with microdissection and amplified with PCR using degenerate oligonucleotide primers. Fluorescence in situ hybridization (FISH) of the PCR product to normal metaphases showed one pair of acrocentrics hybridized, more or less uniformly, along the length of the long arm with an unhybridized gap in the distal region, indicative of an interstitial deletion. Sequential FISH and G-banding of the same chromosome preparations conclusively demonstrated that the deleted segment was 13q22-q32. Four cases of del(13)(q22q32) have been previously reported. The common findings in all five cases, including the present one, are psychomotor and growth retardation, as well as hand and foot anomalies.     

Intercalary deletions of 9q]

Two interstitial deletions of different segments of 9q are reported. The first deletion (9/11q22) was seen in an 8-year-old boy with severe psychomotor retardation and descrete facial dysmorphism. The second deletion (9q32q34) was seen in a 5-month-old boy with a very peculiar cranio-facial dysmorphism including brachycephaly, frontal bossing, a deep nasal bridge, a short nose, and absence of triradii b, c and d.     

Dissection of an inverted X(p21.3q27.1) chromosome associated with mental retardation

In a 6 year old boy referred for mental retardation, fragile X syndrome was ruled out by cytogenetic and molecular analyses. Cytogenetic investigations revealed an inverted X chromosome (p21.3q27.1). A similar chromosomal rearrangement was detected in his mildly mentally retarded mother. Fluorescence in situ hybridization (FISH), using a panel of ordered YAC clones, allowed the identification of YACs spanning both the Xp21.3 and Xq27.1 breakpoints, where many non-specific mental retardation loci have been reported so far. Further investigations by FISH showed that the IL1RAPL1 gene at Xp21.3 was disrupted by the X chromosome inversion and therefore its inactivation may be related to the mental retardation observed in our patients.