New insights into the phenotypes of 6q deletions

Deletions of chromosome 6q are rare. We report 3 new patients with 6q deletions. Case 1 is a male with an interstitial deletion [del(6)(q13q14.2)], hypotonia, speech delays, and minor anomalies. Case 2 is a male with an interstitial deletion [del(6)(q16.2q22.32)] and malformations, including truncus arteriosus and bilateral oligodactyly. Case 3 is a male with a terminal deletion [del(6)(q25.2)] with retinal pits, hydrocephalus, atrioventricular canal, and hydronephrosis. The findings in our patients and those from 57 previously reported cases demonstrated 3 phenotypic groups associated with 6q deletions. Group A [del(6)(q11–q16)] had a high incidence of hernias, upslanting palpebral fissures, and thin lips with lower frequency of microcephaly, micrognathia, and heart malformations. Group B [del(6)(q15–q25)] was associated with increased intrauterine growth retardation, abnormal respiration, hypertelorism, and upper limb malformations. Group C [del(6)(q25-qter)] was associated with retinal abnormalities, cleft palate, and genital hypoplasia. The only universal finding among all patients with 6q deletions was mental retardation. Other findings common to all 3 groups included ear anomalies (90%), hypotonia (82%), and postnatal growth retardation (68%). Am. J. Med. Genet. 70:377–386, 1997. © 1997 Wiley-Liss, Inc.     

Subtle overlapping deletions in the terminal region of chromosome 6q24.2-q26: Three cases studied using FISH

Interstitial deletions in the terminal region of chromosome 6 are rare. We describe three new cases with subtle interstitial deletions in the q24-q26 region of the long arm of chromosome 6. The karyotypes were analyzed at a 550 band level. Patient1 is a 9-month-old boy with an interstitial deletion, del(6)(q24.2q25.1), developmental delay, low birth weight, hypotonia, heart murmur, respiratory distress, craniofacial and genital anomalies. This is the first report of a case with deletion del(6)(q24.2q25.1). Patient 2 is a 17-year-old young man with an interstitial deletion del(6)(q25.1q25.3), developmental delay, short stature, mental retardation, autism, head, face, chest, hand and feet anomalies and a history of seizures. For the first time autism was described as a manifestation in 6q deletions. Patient 3 is baby boy with a de novo interstitial deletion, del(6)(q25.1q26), anomalies of the brain, genital organs, limbs and feet. This is the first report of a case with deletion, del(6)(q25.1q26). In all three patients, fluorescence in situ hybridization (FISH) using chromosome 6 painting probe ruled out an insertion. The ESR (6q25.1) and TBP (6q27) probes were used to confirm the breakpoints. Since TBP signal is present in all cases, it confirmed an interstitial deletion proximal to this probe. Patient 1 has a deletion of the ESR locus; Patient 2 and 3 have signals for the ESR locus on both chromosomes 6. Therefore the deletion in Patients 2 and 3 are between ESR and TBP loci distal to that of Patient 1. FISH validated the deletion breakpoints assessed by conventional cytogenetics. Am. J. Med. Genet. 87:17–22, 1999. © 1999 Wiley-Liss, Inc.     

Fine mapping of breakpoints in two unrelated patients with rare overlapping interstitial deletions of 9q with mild dysmorphic features

Approximately, 20 cases of interstitial deletions of 9q have been reported in the literature spanning the breakpoints from 9q21 to 9q34. Unlike the 9q subtelomeric deletions, the interstitial deletions do not demonstrate a specific recognizable phenotype, although the majority of patients had microcephaly. Lack of precise molecular delineation of the extent of deletions in the published cases makes it difficult to develop an accurate genotype-phenotype correlation. We report on fine mapping of breakpoints using the Affymetrix Human Mapping 500K Array Set in two unrelated female patients with overlapping de novo deletion in 9q. SNP oligonucleotide microarray analysis (SOMA) indicated these to be relatively large deletions with Patient 1 having a 6.47 Mb deletion (>60 genes) spanning 9q32-q33.2 and Patient 2 having a 9.68 Mb deletion (>20 genes) localized to 9q31.1-q33.1. FISH analysis with BAC clones localized to the breakpoints showed discrepant results in Patient 1. Based on the review of previously reported interstitial 9q deletion patients and our patients, the minimal region of overlap (MRO) appears to encompass the 9q32 region and a phenotype characterized by microcephaly, neurological dysfunction and facial dysmorphism can be deduced. Our study shows the investigative nature of the latest array technology and the limitations of this technology in the accurate delineation of breakpoints.     

Characterization of a 16 Mb interstitial chromosome 7q21 deletion by tiling path array CGH

We report on a 42-year-old female patient with an interstitial 16 Mb deletion in 7q21.1-21.3 and a balanced reciprocal translocation between chromosomes 6 and 7 [karyotype 46,XX,t(6;7)(q23.3;q32.3)del(7)(q21.1q21.3)de novo]. We characterized the size and position of the deletion by tiling path array comparative genomic hybridization (CGH), and we mapped the translocation breakpoints on chromosomes 6 and 7 by FISH. The clinical features of this patient-severe mental retardation, short stature, microcephaly and deafness-are in accordance with previously reported patients with 7q21 deletions. Chromosome band 7q21.3 harbors a locus for split hand/split foot malformation (SHFM1), and part of this locus, including the SHFM1 candidate genes SHFM1, DLX5, and DLX6, is deleted. The absence of limb abnormalities in this patient suggests either a location of the SHFM1 causing factor distal to this deletion, or reduced penetrance of haploinsufficiency of a SHFM1 factor within the deleted interval.     

A 5.3Mb deletion in chromosome 18q12.3 as the smallest region of overlap in two patients with expressive speech delay

Interstitial 18q deletions encompassing band 18q12.3 define the del(18)(q12.2q21.1) syndrome. Usual manifestations are mild dysmorphic features, mental retardation, behaviour abnormalities and lack of serious malformation. Seizures have also been found. Recently, more specifically, impairment of expressive language has been reported. We report on two patients with de novo 18q interstitial deletions characterized by oligonucleotide array CGH. The smallest, a 5.3Mb deletion (35.7-40.9Mb) within band q12.3, was found in a 4-year-old girl who suffered mainly from expressive dysphasia. A larger 9.5Mb deletion (34.6-43.9Mb) was observed in a 20-year-old man with a more severe clinical picture including seizures and limited speech. Among the four genes located in the 5.3Mb region, RIT2 (Ras-like without CAAX 2) and SYT4 (synaptotagmin IV), both strongly expressed in the brain, are pointed out as likely candidate genes for language development.     

Interstitial deletion of 14q24.3-q32.2 in a male patient with plagiocephaly, BPES features, developmental delay, and congenital heart defects

Distal interstitial deletions of chromosome 14 involving the 14q24‐q23.2 region are rare, and only been reported so far in 20 patients. Ten of these patients were analyzed both clinically and genetically. Here we present a de novo interstitial deletion of chromosome 14q24.3‐q32.2 in a male patient with developmental delay, language impairment, plagiocephaly, BPES features (blepharophimosis, ptosis, epicanthus), and congenital heart defect. The deletion breakpoints were fine mapped using fluorescence in situ hybridization (FISH) and the size of the deletion is estimated to be approximately 23 Mb. Based on genotype–phenotype comparisons of the 10 previously published patients and the present case, we suggest that the shortest regions for deletion overlap may include candidate genes for speech impairment, mental retardation, and hypotonia. © 2010 Wiley‐Liss, Inc.     

Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11

Interstitial deletions of chromosome band 10q22 are rare. We report on the characterization of three overlapping de novo 10q22 deletions by high-resolution array comparative genomic hybridization in three unrelated patients. Patient 1 had a 7.9 Mb deletion in 10q21.3–q22.2 and suffered from severe feeding problems, facial dysmorphisms and profound mental retardation. Patients 2 and 3 had nearly identical deletions of 3.2 and 3.6 Mb, the proximal breakpoints of which were located at an identical low-copy repeat. Both patients were mentally retarded; patient 3 also suffered from growth retardation and hypotonia. We also report on the results of breakpoint analysis by array painting in a mentally retarded patient with a balanced chromosome translocation 46,XY,t(10;13)(q22;p13)dn. The breakpoint in 10q22 was found to disrupt C10orf11, a brain-expressed gene in the common deleted interval of patients 1–3. This finding suggests that haploinsufficiency of C10orf11 contributes to the cognitive defects in 10q22 deletion patients.     

Interstitial 6q deletion: clinical and array CGH characterisation of a new patient

We report on a patient with an interstitial 6q deletion presenting with moderate mental retardation, persisting hypotonia, facial dysmorphism, but no internal malformations. Standard cytogenetic analysis identified a de novo interstitial 6q deletion. Molecular karyotyping using a 1 Mb array estimated the size of the deletion at approximately 14 Mb encompassing band q16 of chromosome 6. This case report illustrates how the molecular delineation enables improved genotype-phenotype correlations of chromosomal abnormalities to be made and may improve medical care and genetic counselling in individuals with chromosomal imbalances.     

De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature

Patients with distal deletions of chromosome 1q have a recognizable syndrome that includes microcephaly, hypoplasia or agenesis of the corpus callosum, and psychomotor retardation. Although these symptoms have been attributed to deletions of 1q42-1q44, the minimal chromosomal region involved has not yet defined. In this report, we describe a 7 years old male with mental retardation, cryptorchid testes, short stature and alopecia carrying only an interstitial de novo deletion of 911 Kb in the 1q43 region (239,597,095-240,508,817) encompassing three genes CHRM3, RPS7P5 and FMN2.     

A 3 Mb deletion in 14q12 causes severe mental retardation, mild facial dysmorphisms and Rett-like features

The present report describes a 7-year-old girl with a de novo 3 Mb interstitial deletion of chromosome 14q12, identified by oligo array-CGH. The region is gene poor and contains only five genes two of them, FOXG1B and PRKD1 being deleted also in a previously reported case with a very similar phenotype. Both patients present prominent metopic suture, epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears and a clinical course like Rett syndrome, including normal perinatal period, postnatal microcephaly, seizures, and severe mental retardation. FOXG1B (forkhead box G1B) is a very intriguing candidate gene since it is known to promote neuronal progenitor proliferation and to suppress premature neurogenesis and its disruption is reported in a patient with postnatal microcephaly, corpus callosum agenesis, seizures, and severe mental retardation.     

A 10.46 Mb 12p11.1-12.1 interstitial deletion coincident with a 0.19 Mb NRXN1 deletion detected by array CGH in a girl with scoliosis and autism

We present a 12-year-old girl with de novo karyotype 46,XX,del(12)(p11.1p12.1). Array CGH revealed in addition to a 10.466 Mb interstitial deletion on 12p11.1→12p12.1 a 0.191 Mb deletion on 2p16.3. The girl presented with mild facial dysmorphism consisting of microcephaly, hypertelorism, downslanting palpebral fissures, strabismus, broad nasal base, bulbous nose, short philtrum, micro/retrognathia, irregular tooth arrangement, phalangeal deformity in distal phalanges of hands, 5th finger camptodactyly, brachydactyly in feet, history of joint hypermobility, and scoliosis. She was considered to have mild to moderate mental retardation and ascertained for an autism spectrum disorder(ASD). Short arm of chromosome 12 interstitial deletions are rarely reported whereas point mutations and deletions of NRXN1, which is located on chromosome 2p16.3, are associated with ASDs. In this article we present and discuss the phenotypic consequences of a patient who was affected by deletions of two different chromosomal regions.     

Two chromosome aberrations in the child of a woman with systemic lupus erythematosus treated with azathioprine and prednisone

A boy with microcephaly, unusual facial features, micropenis, and growth retardation was born to a 30-year-old woman who took azathioprine and prednisone before and during pregnancy for systemic lupus erythematosus. The child has two apparently de novo chromosomal abnormalities: an apparently balanced translocation between chromosomes 6 and 14 and an interstitial deletion of chromosome 7. The karyotype is 46,XY,del(7)(q21);t(6;14)(q21;q12). Use of azathioprine and prednisone in pregnancy has been associated with intrauterine growth retardation, congenital malformations, and transient chromosome breaks in the blood of newborns. To our knowledge, this is the first report of de novo constitutional chromosome abnormalities in such an infant. We suggest that the assessment of infants born to parents treated with azathioprine should include a chromosome study, even if the infants seem to be normal.     

Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: analysis of 13 patients with a de novo deletion

We performed clinical, cytogenetic, and molecular analyses on 13 patients (8 females and 5 males, aged 6 months to 13 years) with Wolf-Hirschhorn syndrome due to de novo deletions of chromosome 4p. All patients presented with the typical facial gestalt, microcephaly, and profound mental retardation. Other clinical signs were low birth weight (10/13; 77%), postnatal short stature (8/12; 66%), muscular hypotonia (12/13; 92%), seizures (11/13; 85%), congenital heart defects (4/13; 31%), colobomata of iris (4/12; 33%), genital anomalies (4/13; 31%), deafness (3/13; 23%), and renal anomalies (3/13; 23%). The smallest deletion was a submicroscopic terminal deletion of nearly 2.5 Mb. The largest was a terminal deletion of nearly 30 Mb. Cleft lip/palate, preauricular pits/tags, and congenital heart defects were present only in patients with terminal deletions larger than 10 Mb. The deviations from mean birth weight, birth length, and postnatal head circumference correlated with the size of the deletion. Determining the parental origin of the deletion with microsatellite markers, the maternal allele was missing in three patients and the paternal allele in eight patients. Our observations support the existence of a partial genotype-phenotype correlation in Wolf-Hirschhorn syndrome.     

Minimal clinical expression of the holoprosencephaly spectrum and of Currarino syndrome due to different cytogenetic rearrangements deleting the Sonic Hedgehog gene and the HLXB9 gene at 7q36.3

We report clinical, cytogenetic, and molecular cytogenetic studies on four patients with subtle or submicroscopic 7q36 deletions either of de novo origin or resulting from a cryptic parental translocation. Fluorescence in situ hybridization (FISH) studies indicated that in all four patients, the Sonic Hedgehog gene (SHH) and the homeobox gene HLXB9, among others, are comprised in the deletions. Besides mental retardation and short stature, all patients showed only minimal manifestations of the holoprosencephaly (HPE) spectrum and only one displayed symptoms of the Currarino syndrome. Patient 1 had a de novo 7q36.1-qter deletion and showed microcephaly, ptosis, sacral agenesis, tethered cord, but no structural brain anomaly. Patient 2 had a submicroscopic de novo 7q36 deletion detected by FISH, and showed facial and cerebral microsigns of the HPE spectrum. Patient 3 had a 7q36 deletion found by subtelomere FISH testing that was the unbalanced product of a subtle maternal 7q;10q translocation. She presented facial and ocular microsigns, but no structural abnormality of the brain. Patient 4 showed no specific syndromal pattern and was found to have a cryptic unbalanced de novo translocation of the terminal parts of chromosomes 7q and 9p by subtelomere FISH. Patients 2, 3, and 4 represent the first report of a de novo submicroscopic 7q36 deletion, the second report of a familial subtle translocation of 7q36, and the first report of an unbalanced de novo submicroscopic translocation of 7q36, respectively. Our results stress the importance of 7q36 deletion studies by FISH in patients with microsigns of the HPE spectrum.     

A case of de novo interstitial deletion of chromosome 5(q33q34)

The present paper describes a girl with a small de novo deletion of chromosome 5(q33q34). Fluorescence in situ hybridisation with locus specific probes was used to define the extent of this deletion. Clinical features in this patient are microcephaly, dysmorphic facial features such as epicanthus, small biparietal distance and retrognathia, four-finger lines on both hands and mild mental retardation.     

Molecular cytogenetic analysis of a de novo interstitial chromosome 10q22 deletion

Interstitial deletions of 10q are rare, and only one patient with a deletion confined to chromosome band 10q22 has been reported so far. We report on a 2 6/12-year-old girl with a constitutional interstitial deletion of one homologue of 10q [karyotype: 46,XX,del(10)(q22.2q22.3)de novo]. Our patient had muscular hypotonia, developmental delay, growth retardation, mild facial dysmorphism, and hypoplastic labia minora. The precise location and extent (3.6 Mb) of the deletion was determined by fluorescence in situ hybridization (FISH) using 16 YAC and BAC clones. The clinical features in our patient are remarkably similar to the previously reported patient with a 10q22.2 deletion.     

Clinical features in a de novo interstitial deletion 15q13 to q15

A boy with several dysmorphic features and suffering from mental and motor retardation was found to have a de novo interstitial deletion of chromosome 15, involving bands q13 to q15. His clinical picture is described and compared with the clinical features reported in other deletions of this chromosome, located or extending distally from the region associated with Prader-Willi syndrome.     

Interstitial deletion 2q33.3-q34 in a boy with a phenotype resembling the Seckel syndrome

A boy presented at 5 weeks with a syndrome of pre- and postnatal growth retardation, microcephaly, muscular hypotonia, and facial anomalies resembling those seen in Seckel syndrome or microcephalic primordial dwarfism I. Analysis of prometaphase chromosomes, fluorescent in situ hybridization (FISH), and molecular studies showed the presence of a de novo chromosome 2 deletion that could be defined as del(2)(q33.3q34)pat. Parental chromosomes were normal, except for the presence of a paternal supernumerary marker identified by FISH as der(15). On follow-up of the patient during the next months length development appeared normal and the diagnosis of Seckel syndrome was withdrawn. Clinical findings of previously published cases with interstitial deletion of at least 2q33.3-q34, the deletion present in the propositus, are reviewed and include pre- and postnatal growth retardation, psychomotor retardation, microcephaly, micrognathia, and abnormal/low-set ears; findings also present in the propositus. These findings resemble those described in the Seckel syndrome. Noteworthy is the finding that 2/3 of the 60 reviewed cases originally reported as having Seckel syndrome apparently belong to a heterogeneous group of low birth weight microcephalic dwarfism I yet to be clearly defined. In these patients no chromosome 2q deletion has been reported so far. Retrospective analysis could show if a subgroup of these patients carry submicroscopic deletions at 2q33.3-q34. Alternatively, molecular analysis of this region may be warranted in newly diagnosed patients with Seckel syndrome- like manifestations. Am. J. Med. Genet. 71:479–485, 1997. © 1997 Wiley-Liss, Inc.     

2q24-q31 deletion: report of a case and review of the literature

We report a patient with a de novo interstitial deletion of the long arm of chromosome 2 involving bands 2q24.3-q31.1. The patient shows postnatal growth retardation, microcephaly, ptosis, down-slanting palpebral fissures, long eyelashes and micrognathia. Halluces are long, broad and medially deviated, while the other toes are laterally deviated and remarkably short with hypoplastic phalanges. She also showed developmental delay, seizures, lack of eye contact, stereotypic and repetitive hand movements and sleep disturbances with breath holding. Prenatal and three independent postnatal karyotypes were normal. Array-CGH analysis allowed us to identify and characterize a "de novo" 2q interstitial deletion of about 10.4Mb, involving segment between cytogenetic bands 2q24.3 and 2q31.1. The deletion was confirmed by quantitative PCR. About 30 children with 2q interstitial deletion have been reported. The deletion described here is overlapping with 15 of these cases. We have attempted to compare the clinical features of our patient with 15 overlapping cases. The emerging phenotypes include low birth weight, postnatal growth retardation, mental retardation and developmental delay, microcephaly, and peculiar facial dysmorphisms. Peculiar long and broad halluces with an increased distance between the first and the second toe are ("sandal gap" sign) present in most of the described patients. The gene content analysis of the deleted region revealed the presence of some genes that may be indicated as good candidates in generating both neurological and dysmorphic phenotype in the patient. In particular, a cluster of SCNA genes is located within the deleted region and it is known that loss of function mutations in SCNA1 gene cause a severe form of epilepsy.