Identification of a missense mutation of c.3064G>A, Gly1022Ser in exon 43 of COL1A1 gene in a girl with osteogenesis imperfecta type III.

Osteogenesis imperfecta (OI) types I-V have been inherited in an autosomal dominant pattern. OI type I is associated with mutations in COL1A1 mostly due to a null allele. OI types II-IV are associated with mutations in COL1A1 or COL1A2 and mostly are due to glycine substitutions. It has been suggested that the effect of glycine substitutions is position specific, and the substitution of glycine by serine has much less lethal effect than the substitutions by valine, aspartic acid, glutamic acid, arginine and cysteine. We report identification of c.3064G>A, GGT>AGT, Gly1022Ser (Gly(844) --> Ser844 in triple helix) in exon 43 of the COL1A1 gene in an 8-year-old girl with OI type III. Our report provides evidence that at triple helix glycine residue 844 (p.Gly1022), a glycine substitution by serine can result in OI type III but not a lethal outcome.

Partial monosomy 3p (3p26.2 --> pter) and partial trisomy 5q (5q34 --> qter) in a girl with coarctation of the aorta, congenital heart defects, short stature, microcephaly and developmental delay.

A 1-year-and-3-month-old girl presented with psychomotor retardation, developmental delay, clinodactyly of the thumb, coarctation of the aorta, patent ductus arteriosus, peripheral pulmonary stenosis, atrial septal defect, microcephaly, brachycephaly, a small oval face, almond-shaped eyes, a down-turned mouth, a widened nasal bridge, hypertelorism, epicanthic folds, long philtrum, low-set large ears and but no craniosynostosis. Oligonucleotide-based array comparative genomic hybridization revealed a -4.79-Mb deletion of 3p26.2 --> pter encompassing CHL1 and CNTN4, and a -19.56-Mb duplication of 5q34 --> qter encompassing MSX2, NKX2-5 and NSD1. The karyotype of the girl was 46,XX,der(3)t(3;5)(p26.2;q34) pat. The present case adds distal 5q duplication to the list of chromosome aberrations associated with coarctation of the aorta.

Phenotypic features of pure 9p deletion in a male infant include cryptorchidism, congenital heart defects and postaxial polydactyly.

We report a 2 1/2-year-old male infant with a karyotype of 46,XY,del(9)(p22) and the phenotypic features of craniofacial dysmorphisms, hypotonia, psychomotor developmental delay, mental retardation, ventricular septal defect, atrial septal defect, cryptorchidism and postaxial polydactyly of the fingers. A rudimentary poorly developed extra digit in the ulnar side of the fifth finger was observed in each hand. The present case adds to the literature of postaxial hexadactyly of the fingers in chromosome 9p deletion syndrome. We suggest that 9pter-p22 may contain genetic loci associated with human postaxial polydactyly.

Pure distal 9p deletion in a female infant with cerebral palsy.

We report cytogenetic and molecular characterization of a 15.63-Mb pure distal deletion of chromosome 9p (9p22.3-->pter) in a l 1/2-year-old female infant with cerebral palsy and diffuse cerebral dysfunction. The deletion is of paternal origin and encompasses the genes of ANKRDS15, DOCK8, FOXD4 and VLDLR. We discuss the genotype-phenotype correlation in this case with neurological dysfunction and a distal 9p deletion of paternal origin.

Pure distal 11q deletion without additional genomic imbalances in a female infant with Jacobsen syndrome and a de novo unbalanced reciprocal translocation.

We report a neonate with pure deletion of distal 11q (11q23.3-->qter) and Jacobsen syndrome. The patient had growth restriction, petechiae, thrombocytopenia, dilation of renal pelvis, congenital heart defects, and seizures. Array comparative genomic hybridization revealed a 15.8-Mb deletion from 11q23.3 to 11q25 without genomic imbalances in other chromosomes. Cytogenetic analysis revealed a karyotype of 46,XX,der(7)(7pter-->7q32),der(11)(11pter--> 11q23.3::7q32-->7qter). The parental karyotypes were normal. This is the first report of pure distal 11q deletion without additional genomic imbalances in a patient with Jacobsen syndrome and a de novo unbalanced reciprocal translocation.

Partial trisomy 1q (1q42.13-->qter) and partial monosomy 6q (6q27-->qter) in a girl with single median maxillary central incisor, corpus callosum dysgenesis and developmental delay.

A 3-year-old girl presented with mental retardation, developmental delay, seizures, hypotonia, brachycephaly, a triangular face, single median maxillary central incisor (SMMCI), prominent forehead, down-slanting palpebral fissures, hypertelorism, a high-arched palate, micrognathia and low-set ears. Computed tomographic scans revealed corpus callosum dysgenesis and hypoplasia of bilateral frontal sinuses. Oligonucleotide-based array comparative genomic hybridization analysis revealed a -20.7-Mb duplication of 1q42.13-->qter and a -3.6-Mb deletion of 6q27-->qter. The karyotype of the girl was 46,XX,der(6)t(1;6)(q42.13;q27)pat. Mutational analysis of the patient revealed no mutation in the genes of SHH, SIX3 and TGIF. The present case adds unbalanced chromosome aberration of partial trisomy 1q and partial monosomy 6q to the list of genetic conditions associated with SMMCI.

De novo satellited 2q associated with corpus callosum dysgenesis, short stature, mental retardation and developmental delay.

We report the cytogenetic and molecular characterization of a 9.46-Mb terminal deletion of 2q in a 3-year-old girl with a de novo satellited 2q (2qs), corpus callosum dysgenesis, short stature, mental retardation and developmental delay. We speculate that haploinsufficiency of HDAC4 is responsible for short stature, mental retardation and developmental delay, and haploinsufficiency of EFHD1 is most likely responsible for the phenotype of corpus callosum dysgenesis in this patient.

A 24.2-Mb deletion of 4q12 --> q21.21 characterized by array CGH in a 131/2-year-old girl with short stature, mental retardation, developmental delay, hyperopia, exotropia, enamel defects, delayed tooth eruption and delayed puberty.

We report molecular and cytogenetic characterization of proximal deletion of chromosome 4q, del(4)(q12 --> q21.21) in a 131/2-year-old girl with short stature, mental retardation, developmental delay, hyperopia, exotropia, enamel defects, delayed tooth eruption and delayed puberty. We speculate that haploinsufficiency of the AMTN, ENAM and AMBN genes is most likely responsible for dental disorders, haploinsufficiency of the BMP2K genes is most likely responsible for ocular disorders, and haploinsufficiency of the EREG, AREG and BTC genes is most likely responsible for delayed puberty in this patient.

Mosaic supernumerary r(1)(p13.2q23.3) in a 10-year-old girl with epilepsy facial asymmetry psychomotor retardation kyphoscoliosis dermatofibrosarcoma and multiple exostoses.

We report molecular cytogenetic characterization of mosaic supernumerary r(1)(p13.2q23.3) in a 10-year-old girl with epilepsy, facial asymmetry, psychomotor retardation, kyphoscoliosis, dermatofibrosarcoma and multiple exostoses. The supernumerary r(1) is associated with gene dosage increase of CHRNB2, ADAR and KCNJ10 in the pericentromeric area of 1q, and a breakpoint within CTTNBP2NL at 1p13.2. We speculate that the gene dosage increase of CHRNB2, ADAR and KCNJ10 is most likely responsible for epilepsy, and the breakpoint at 1p13.2 in the supernumerary r(1) is most likely responsible for the development of multiple exostoses and osteochondroma in this patient.

Pure interstitial duplication of chromosome 7q (7q31.2-->q33) in a 4-year-old girl with growth restriction, short stature, speech delay and intellectual disability.

We report the cytogenetic and molecular characterization of a 22.3-Mb pure interstitial duplication of chromosome 7q, dup(7)(q31.2-->q33) in a 4-year-old girl with growth restriction, short stature, speech delay, inguinal hernia, strabismus and intellectual disability. We speculate that the gene dosage increase effect of the ING3 and LEP genes may be partially responsible for the phenotype of growth restriction and short stature in this patient.