Siblings with opposite chromosome constitutions,dup(2q)/del(7q) and del(2q)/dup(7q)

Chromosome 7q36 microdeletion syndrome is a rare genomic disorder characterized by underdevelopment of the brain, microcephaly, anomalies of the sex organs, and language problems. Developmental delay, intellectual disability, autistic spectrum disorders, BDMR syndrome, and unusual facial morphology are the key features of the chromosome 2q37 microdeletion syndrome. A genetic screening for two brothers with global developmental delay using high-resolution chromosomal analysis and subtelomeric multiplex ligation-dependent probe amplification revealed subtelomeric rearrangements on the same sites of 2q37.2 and 7q35, with reversed deletion and duplication. Both of them showed dysmorphic facial features, severe disability of physical and intellectual development, and abnormal genitalia with differential abnormalities in their phenotypes. The family did not have abnormal genetic phenotypes. According to the genetic analysis of their parents, adjacent-1 segregation from their mother's was suggested as a mechanism of their gene mutation. By comparing the phenotypes of our patients with previous reports on similar patients, we tried to obtain the information of related genes and their chromosomal locations.     

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.     

Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping

We report four new patients with a submicroscopic deletion in 15q24 manifesting developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, and characteristic facial features. These clinical features are shared with six recently reported patients with a 15q24 microdeletion, supporting the notion that this is a recognizable syndrome. We describe a case of an ~2.6 Mb microduplication involving a portion of the minimal deletion critical region in a 15-year-old male with short stature, mild mental retardation, attention deficit hyperactivity disorder, Asperger syndrome, decreased joint mobility, digital abnormalities, and characteristic facial features. Some of these features are shared with a recently reported case with a 15q24 microduplication involving the minimal deletion critical region. We also report two siblings and their mother with duplication adjacent and distal to this region exhibiting mild developmental delay, hypotonia, tapering fingers, characteristic facial features, and prominent ears. The deletion and duplication breakpoints were mapped by array comparative genomic hybridization and the genomic structure in 15q24 was analyzed further. Surprisingly, in addition to the previously recognized three low-copy repeat clusters (BP1, BP2, and BP3), we identified two other paralogous low-copy repeat clusters that likely mediated the formation of alternative sized 15q24 genomic rearrangements via non-allelic homologous recombination.     

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.     

A de novo 2.3 Mb deletion in 2q24.2q24.3 in a 20-month-old developmentally delayed girl

We report a 20-month-old girl ascertained at the age of 11 months for developmental delay. She presented with hypotonia and delayed motor development. The patient had severe language impairment and showed behaviour consistent with autism spectrum disorder. She was microcephalic with mild dysmorphic features and had joint hyperlaxity. We detected a 2.3 Mb de novo deletion in 2q24.2q24.3 on her paternal chromosome.     

An unusual clinical characterization of a male with distal partial trisomy 1q42.1 and monosomy 4q35.1 and review of the literature

We report a male patient with a karyotype of 46,XY, der(4)t(1;4)(q42.1;q35.1) inherited from a maternal balanced translocation involving chromosome 1q and 4q. The boy had corpus callosum dysgenesis, laryngomalacia, tracheobronchus, facial dysmorphism, simian creases, and developmental retardation. The first three features are unique compared to previous literature reports on distal partial trisomy 1q. This case report allows a further delineation of the distal partial trisomy 1q syndrome.     

Clinical and cytogenetic study of a case with familial chromosomal translocation presenting with facial dysmorphism and axial neuropathy

We report on a 9-year-old female patient presenting with muscle weakness, facial dysmorphism and mild mental retardation. She had low birth weight, developmental delay, hypotonia and hyporeflexia and difficulties in climbing the stairs. EMG revealed axonal polyneuropathy affecting both upper and lower limbs. She was the child of non-consanguineous parents, her cytogenetic findings revealed 46,XX,t(12;14)(q14;q23). The mother's karyotype was normal 46,XX while the father's karyotype was 46,XY,t(12;14)(q14;q23) the same as his daughter. Her normal sister's karyotype was also 46,XX,t(12; 14) (q14;q23). Fluorescence in situ hybridization (FISH) was used to elucidate the breakpoints and Array-CGH was done for the patient to confirm the balanced translocation. This observation is of interest because it represents a rare case of a balanced translocation with abnormal phenotype. Mutant genes causing axonal neuropathy have been located on various chromosomes other than 12q14 or 14q24. This report shows the importance of molecular cytogenetics and its correlation with abnormal phenotype and the possibility of another gene locus at the presently studied chromosomal breakpoints. Detailed correlations between chromosome aberrations and their phenotypes are of invaluable help in localising genes for axonal polyneuropathy.     

A de novo 3p13 deletion induced by a complex chromosomal rearrangement combined with a pericentric inversion of chromosome,inv(3)(p13q12), and a translocation between chromosome 3 and 8, t(3;8)(q13.1;q24.2), in a child with developmental delay

A de novo complex chromosomal rearrangement is very rare but likely to be present in a child with developmental disabilities and physical alterations. A child presented in this study showed global developmental delay and some typical phenotypes. Initial karyotyping and FISH analysis in the patient showed an apparently de novo balanced translocation between chromosome 3 and 8, t(3;8)(q13.1;q24.2). Further analysis using multiplex ligation-dependent probe amplification and array-based comparative genomic hybridization revealed a cryptic microdeletion on 3p13 region. Nearly one-third of balanced rearrangements are reported to involve cryptic disruptions at breakpoints, however, the microdeletion of the proposita was present in non-translocated region of the chromosome 3. After careful reevaluation of the results, a pericentric inversion, inv(3)(p13q13.1) that induced deletion was revealed. The clinical features of developmental delay in cognition, language, and motor function and facial and physical phenotype of the proposita were similar to those found in the children with 3p13 deletion. This case shows that combined molecular cytogenetic techniques with routine karyotyping are very useful to identify subtle genomic changes associated with abnormal phenotypes.     

A Genotype-First Approach for the Molecular and Clinical Characterization of Uncommon De Novo Microdeletion of 20q13.33

Background

Subtelomeric deletions of the long arm of chromosome 20 are rare, with only 11 described in the literature. Clinical features of individuals with these microdeletions include severe limb malformations, skeletal abnormalities, growth retardation, developmental and speech delay, mental retardation, seizures and mild, non-specific dysmorphic features.

Methodology/Principal Findings

We characterized microdeletions at 20q13.33 in six individuals referred for genetic evaluation of developmental delay, mental retardation, and/or congenital anomalies. A comparison to previously reported cases of 20q13.33 microdeletion shows phenotypic overlap, with clinical features that include mental retardation, developmental delay, speech and language deficits, seizures, and behavior problems such as autistic spectrum disorder. There does not appear to be a clinically recognizable constellation of dysmorphic features among individuals with subtelomeric 20q microdeletions.

Conclusions/Significance

Based on genotype-phenotype correlation among individuals in this and previous studies, we discuss several possible candidate genes for specific clinical features, including ARFGAP1, CHRNA4 and KCNQ2 and neurodevelopmental deficits. Deletion of this region may play an important role in cognitive development.     

Pure distal monosomy 10q26 in a patient displaying clinical features of Prader-Willi syndrome during infancy and distinct behavioural phenotype in adolescence

A male patient is reported with terminal 10q26 deletion and clinical findings suggesting Prader-Willi syndrome during the infancy. These findings included decreased fetal movements, neonatal hypotonia, need for tube feeding, characteristic facial dysmorphism with dolichocephaly, narrow bifrontal diameter, almond-shaped eyes and epicanthus, hypogenitalism and developmental retardation. However, during the further evolution there was neither hyperphagia nor obesity and chromosomal and molecular investigations failed to confirm the diagnosis of Prader-Willi syndrome. Special behavioural abnormalities became evident with notably hyperactivity, hyperkinesis and destructive tendency. Finally, at the age of 17 years high resolution chromosome studies revealed a terminal 10q26.3 deletion. A review of the literature is made on previously reported patients with either a Prader-Willi-like syndrome or a terminal 10q deletion with behavioural problems.     

Deletion 11q23-->qter (Jacobsen syndrome). Report of three new patients.

Three unrelated patients with de novo del 11q23-->qter are reported. Clinical features included growth and mental retardation, hypotonia, trigonocephaly, facial dysmorphism with hypertelorism, epicanthal folds, abnormally shaped palpebral fissures, eye globe malformations, depressed nasal bridge, "carp-shaped" mouth, highly arched palate, low set and malformed ears. One patient had congenital heart defect, and reduced platelet count. This syndrome, originally reported by Jacobsen, is now corroborated by more than 35 patients and appears as the most common deletion involving 11q. Since deletion of subband 11q24.1 is critical for full expression of this syndrome, the JBS phenotype could be an example of contiguous gene syndrome.     

A new case of partial 14q31.3-qter trisomy due to maternal pericentric inversion

Chromosome 14 is often involved in chromosome rearrangements, although pericentric inversions are rare. Here we report a mother carrying a pericentric inversion of chromosome 14, and her daughter with recombinant chromosome characterized by a partial distal 14q trisomy. Principal clinical findings of the child include facial anomalies, microcephaly, developmental delay, hypotonia and cardiac malformation. Her final karyotype was 46,XX,rec(14)dup(14q)inv(14)(p12q31)mat[20], arr 14q31.3qter(85,427,839–106,356,482)x3. This report brings new data about clinical features of partial 14q trisomy and molecular analysis enables the visualization of genes involved in the segment duplicated.     

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.     

Cryptic translocation t(5;18) in familial mental retardation

A cryptic translocation t(5;18)(qter;qter) was detected in a large family, using a FISH-based approach combining subtelomeric probes to allow the subtelomeric regions of most chromosome ends to be analysed for deletions and balanced or unbalanced translocations. Unbalanced karyotypes (duplication 5qter/deficiency 18qter) resulted in a previously undescribed association of moderate to severe mental retardation, microcephaly, pre- and postnatal growth retardation, distinct facial dysmorphism, narrow auditory canals, genital hypoplasia, left heart hypoplasia in one patient and severe behaviour difficulties in another. Some of the features observed in affected individuals are characteristic of known syndromes involving either 18q (growth deficiency, nystagmus, narrow auditory canals, genital hypoplasia, behaviour problems in 18q deletion syndrome) or 5q (umbilical and inguinal hernias, congenital heart defects in distal 5q trisomy).     

De novo translocation (2;18)(q21;q22) in a child with severe epilepsy, developmental delay and mild dysmorphism

De novo translocation (2;18)(q21;q22) in a patient with severe epilepsy developmental delay and mild dysmorphism: We report on a patient presenting with severe epilepsy, hypotonia, developmental delay, blepharophimosis, low-set ears, camptodactyly and tapering fingers, and cutaneous syndactyly of toes II and III of the right foot. The MRI showed some loss of volume of the white matter and delayed myelination, no other specific anomalies were present. Chromosome analysis revealed a translocation involving chromosomes 2 and 18, which was characterized further by FISH using band-specific probes. The possibility of a submicroscopic deletion is discussed and the patient is compared with patients reported in the literature with either 2q21 or 18q22 deletion.     

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.     

Distal duplication 14q: Report of three cases and further delineation of the syndrome

Summary Three cases of distal duplication 14q are presented. The first two cases are cousins in a kindred segregating a balanced translocation t(14;18)(q31;q23). The third case resulted from a maternal translocation t(14;18)(q24;p11). By review of these cases and those previously reported, a distal duplication 14q syndrome is further delineated. Common features include postnatal growth retardation, mental retardation, hypotonia, microcephaly, slanted palpebral fissures, ocular hypertelorism, sparse eyelashes and eyebrows, nasal dysmorphism, tented lip, micrognathia, posteriorly rotated ears, and minor skeletal anomalies.     

Partial trisomy 8p (8p11.2-->pTER) and deletion of 13q (13q32-->qTER): case report

We report a female infant with partial trisomy 8p (8p11.2-->pter) and deletion of 13q (13q32-->qter). She was born with mild hypotonia, intrauterine growth retardation, microcephaly, micrognathia, large low set ears, pectus excavatum, anteriorly placed anus, and bilateral clinodactyly. Echocardiography showed left ventricular hypertrophy, bicuspid aortic valve, dilatation of the aorta and pulmonary artery, and prolapse of atrio-venticular valve leaflets. Cytogenetic investigation of her sister and her father showed that the altered region resulted from a balanced translocation between the part of the long arm of chromosome 13 and short arm of chromosome 8. In partial trisomy 8p, the clinical picture of the patients comprises hypotonia, structural brain abnormalities, facial anomalies including a large mouth with a thin upper lip, a high arched palate, a broad nasal bridge, an abnormal maxilla or mandible, malformed, low set ears, and orthopedic anomalies. Although patients with proximal deletions of 13q that do not extend into band q32 have mild to moderate mental and growth delays with variable minor anomalies, patients with more distal deletions including at least part of band q32 usually have major malformations such as retinoblastoma, mental-motor growth retardation, malformation of brain and heart, anal atresia, and anomalies of the face and limbs. To our knowledge partial trisomy 8p and partial monosomy of 13q have not been reported previously in the same person.     

Trisomy 11 q (q23.1 - qter) through maternal translocation t(11;22) (q23.1;q11.1). A new case]

A 4-year-old boy with partial trisomy 11q resulting from malsegregation of a maternal translocation, t(11;22)(q23.1;q11.1), exhibits the following malformations: severe mental deficiency; growth retardation and hypotonia; brachycephaly with flattened occiput and forehead; facial dysmorphia; pre-auricular fistula. These features are in good agreement with the syndrome recently described for partial trisomy 11q. The translocation appears to be identical in that in three other families already reported.     

Deletion 2q37.3 and autism: molecular cytogenetic mapping of the candidate region for autistic disorder

Fine mapping of deletion regions in autistic patients represents a valuable screening tool for identifying candidate genes for autism. A number of studies have ascertained associations between autism and terminal 2q deletion with the breakpoint within 2q37. Here we describe a 12-year-old female patient with terminal 2q37.3 cryptic deletion and autistic behaviour. Her clinical features included hypotonia and feeding difficulties during infancy, coarse face with notably prominent forehead, prominent eyebrows, broad flat nasal bridge and round cheeks, small hands and feet with bilateral brachymetaphalangism, proximal implantation of the thumbs and short toenails, mild mental retardation and autistic behaviour. Recorded autistic features included early lack of eye contact and, during infancy, little social interactions, propensity to be stereotypically busy and to get anxious. In order to more closely delineate the linkage region for autism within 2q37, the findings in this patient were combined to those in 2 previously reported siblings with a well documented 2q37.3 deletion, but without autistic disorder. The exact size of the deleted segment was determined by mapping the deleted region in each group with a series of specific BAC clones linearly ordered on the 2q37 region. The deletion in the autistic patient appeared to be larger [breakpoint flanked by more centromeric clones RP11-680016 (236.9 Mb) and 201F21 (237.4 Mb)] than in the non autistic siblings [more telomeric clones RP11-205L13 (237.8 Mb) and 346114 (238.2 Mb)], revealing a distance of maximum 1.3 Mb between the breakpoints. Accordingly, the extent of the candidate region for susceptibility genes for autism on distal 2q is reduced to maximum 1.3 Mb. Comparison with another well documented autistic patient from the literature results in the same conclusion. These findings represent thus a further step towards identifying genes predisposing to autism.