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.     

3q26.31–q29 duplication and 9q34.3 microdeletion associated with omphalocele,ventricular septal defect,abnormal first-trimester maternal serum screening and increased nuchal translucency: Prenatal diagnosis and aCGH characterization

We present prenatal diagnosis and array comparative genomic hybridization characterization of 3q26.31–q29 duplication and 9q34.3 microdeletion in a fetus with omphalocele, ventricular septal defect, increased nuchal translucency, abnormal first-trimester maternal screening and facial dysmorphism with distinct features of the 3q duplication syndrome and Kleefstra syndrome. The 26.61-Mb duplication of 3q26.31–q29 encompasses EPHB3, CLDN1 and CLDN16, and the 972-kb deletion of 9q34.3 encompasses EHMT1. We review the literature of partial trisomy 3q associated with omphalocele and discuss the genotype–phenotype correlation in this case.     

Molecular characterization of near-complete trisomy 17p syndrome from inverted duplication in association with cryptic deletion of 17pter

Trisomy of the short arm of chromosome 17 (T17P) is a genomic disorder presenting with growth retardation, motor and mental retardation and constitutional physical anomalies including congenital heart defects. Here we report a case of near-complete T17P of which the genomic dosage aberrations were delineated by chromosomal microarray along with conventional diagnostic modalities. A 9-year-old Korean boy was admitted because of esophageal obstruction. He showed clinical manifestations of T17P, along with atypical features of scoliosis, corpus callosum agenesis, and seizure. Chromosome analyses revealed an inverted duplication of the chromosomal segment between 17p11.2 and 17p13.3. Chromosomal microarray revealed a duplication of the most of the short arm of chromosome 17 (size ~ 19.09 Mb) along with a cryptic deletion of a small segment of 17p terminal end (17pter) (~ 261 Kb). This is the first report of molecular characterization of near-complete T17P from inverted duplication in association with 17pter microdeletion. The fine delineation of the extent of genomic aberration by SNP-based microarray could help us better understand the molecular mechanism and genotype–phenotype correlations in T17P syndrome.     

A prenatally ascertained,maternally inherited 14.8 Mb duplication of chromosomal bands Xq13.2–q21.31 associated with multiple congenital abnormalities in a male fetus

Duplications of the X chromosome are rare cytogenetic findings, and have been associated with an abnormal phenotype in the male offspring of apparently normal or near normal female carriers. We report on the prenatal diagnosis of a duplication on the long arm of chromosome X from chromosomal band Xq13.2 to q21.31 in a male fetus with increased nuchal translucency in the first trimester and polyhydramnios at 22 weeks of gestation. Amniocentesis was undertaken and cytogenetic analysis revealed additional chromosomal material in the long arm of chromosome X at position Xq13. Analysis with high resolution array CGH revealed the additional material is in fact a duplication of the region Xq13.2–q21.13. The duplication is 14.8 Mb in size and includes fourteen genes: SLC16A2, KIAA2022, ABCB7, ZDHHC15, ATRX, MAGT1, ATP7A, PGK1, TBX22, BRWD3, POU3F4, ZNF711, POF1B and CHM. Analysis of the parents revealed the mother to be a carrier of the same duplication. After elected termination of the pregnancy at 28 weeks a detailed autopsy of the fetus allowed for genotype–phenotype correlations.     

Prenatal diagnosis of foetuses with congenital abnormalities and duplication of the MECP2 region

MECP2 duplication results in a well-recognised syndrome in 100% of affected male children; this syndrome is characterised by severe neurodevelopmental disabilities and recurrent infections. However, no sonographic findings have been reported for affected foetuses, and prenatal molecular diagnosis has not been possible for this disease due to lack of prenatal clinical presentation. In this study, we identified a small duplication comprising the MECP2 and L1CAM genes in the Xq28 region in a patient from a family with severe X-linked mental retardation and in a prenatal foetus with brain structural abnormalities. Using high-resolution chromosome microarray analysis (CMA) to screen 108 foetuses with congenital structural abnormalities, we identified additional three foetuses with the MECP2 duplication. Our study indicates that ventriculomegaly, hydrocephalus, agenesis of the corpus callosum, choroid plexus cysts, foetal growth restriction and hydronephrosis might be common ultrasound findings in prenatal foetuses with the MECP2 duplication and provides the first set of prenatal cases with MECP2 duplication, the ultrasonographic phenotype described in these patients will help to recognise the foetuses with possible MECP2 duplication and prompt the appropriate molecular testing.     

Angelman syndrome and severe infections in a patient with de novo 15q11.2–q13.1 deletion and maternally inherited 2q21.3 microdeletion

Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, severe speech disorder, facial dysmorphism, secondary microcephaly, ataxia, seizures, and abnormal behaviors such as easily provoked laughter. It is most frequently caused by a de novo maternal deletion of chromosome 15q11–q13 (about 70–90%), but can also be caused by paternal uniparental disomy of chromosome 15q11–q13 (3–7%), an imprinting defect (2–4%) or in mutations in the ubiquitin protein ligase E3A gene UBE3A mostly leading to frame shift mutation. In addition, for patients with overlapping clinical features (Angelman-like syndrome), mutations in methyl-CpG binding protein 2 gene MECP2 and cyclin-dependent kinase-like 5 gene CDKL5 as well as a microdeletion of 2q23.1 including the methyl-CpG binding domain protein 5 gene MBD5 have been described. Here, we describe a patient who carries a de novo 5 Mb-deletion of chromosome 15q11.2–q13.1 known to be associated with Angelman syndrome and a further, maternally inherited deletion 2q21.3 (~ 364 kb) of unknown significance. In addition to classic features of Angelman syndrome, she presented with severe infections in the first year of life, a symptom that has not been described in patients with Angelman syndrome. The 15q11.2–q13.1 deletion contains genes critical for Prader–Willi syndrome, the Angelman syndrome causing genes UBE3A and ATP10A/C, and several non-imprinted genes: GABRB3 and GABRA5 (both encoding subunits of GABA A receptor), GOLGA6L2, HERC2 and OCA2 (associated with oculocutaneous albinism II). The deletion 2q21.3 includes exons of the genes RAB3GAP1 (associated with Warburg Micro syndrome) and ZRANB3 (not disease-associated). Despite the normal phenotype of the mother, the relevance of the 2q21.3 microdeletion for the phenotype of the patient cannot be excluded, and further case reports will need to address this point.     

De novo MECP2 duplication derived from paternal germ line result in dysmorphism and developmental delay

Xq28 duplications encompassing the methyl CpG binding protein 2 (MECP2) in males exhibit a distinct phenotype, including developmental delay, facial dysmorphism, muscular hypotonia, intellectual disability, poor or absent speech, recurrent infections and early death. The vast majority of affected males inherit the MECP2 duplication from their usually asymptomatic carrier mothers. Only a few cases with Xq28 duplication originating from de novo unbalanced X/Y translocation have been reported and the paternal origin of the aberration has only been validated in three males in the related literature. Here we present a karyotypically normal male with features characteristic of the MECP2 duplication syndrome. The genome-wide SNP genotyping shows a de novo 2.26-Mb duplication from Xq28 to the terminus. The genotypes of the SNPs within the duplicated region indicated a paternal origin. Furthermore, the results of fluorescence in situ hybridization (FISH) indicated a novel Xq:Yp translocation, characterized as der(Y)t(Y;X)(p11.32;q28), which suggests an aberrant that occurred during spermatogenesis. The phenotype is compared to the previously reported cases with Xq28 duplication originated from an unbalanced X/Y translocation, and there was no specific part of the phenotype that could be contributed to the origin of parental imbalances. This report further highlights the capacity of high-molecular cytogenetic methods, such as SNP array and FISH, in the identification of submicroscopic rearrangement, structural configuration and parental origin of aberrant while in the evaluation of children with idiopathic developmental delay and intellectual disability.     

A Turkish family with Nance-Horan syndrome due to a novel mutation

Nance-Horan Syndrome (NHS) is a rare X-linked syndrome characterized by congenital cataract which leads to profound vision loss, characteristic dysmorphic features and specific dental anomalies. Microcornea, microphthalmia and mild or moderate mental retardation may accompany these features. Heterozygous females often manifest similarly but with less severe features than affected males. We describe two brothers who have the NHS phenotype and their carrier mother who had microcornea but not cataract. We identified a previously unreported frameshift mutation (c.558insA) in exon 1 of the NHS gene in these patients and their mother which is predicted to result in the incorporation of 11 aberrant amino acids prior to a stop codon (p.E186Efs11X). We also discussed genotype–phenotype correlation according to relevant literature.     

Mosaic small supernumerary marker chromosome 1 at amniocentesis: Prenatal diagnosis,molecular genetic analysis and literature review

We present prenatal diagnosis and molecular cytogenetic analysis of mosaic small supernumerary marker chromosome 1 [sSMC(1)]. We review the literature of sSMC(1) at amniocentesis and chromosome 1p21.1-p12 duplication syndrome. We discuss the genotype–phenotype correlation of the involved genes of ALX3, RBM15, NTNG1, SLC25A24, GPSM2, TBX15 and NOTCH2 in this case.     

Array CGH characterization of an unbalanced X-autosome translocation associated with Xq27.2–qter deletion, 11q24.3–qter duplication and Xq22.3–q27.1 duplication in a girl with primary amenorrhea and mental retardation

We present array comparative genomic hybridization (aCGH) characterization of an unbalanced X-autosome translocation with an Xq interstitial segmental duplication in a 16-year-old girl with primary ovarian failure, mental retardation, attention deficit disorder, learning difficulty and facial dysmorphism. aCGH analysis revealed an Xq27.2–q28 deletion, an 11q24.3–q25 duplication, and an inverted duplication of Xq22.3–q27.1. The karyotype was 46,X,der(X)t(X;11)(q27.2;q24.3) dup(X)(q27.1q22.3). We discuss the genotype–phenotype correlation in this case. Our case provides evidence for an association of primary amenorrhea and mental retardation with concomitant unbalanced X-autosome translocation and X chromosome rearrangement.     

De novo 3q22.1 q24 deletion associated with multiple congenital anomalies,growth retardation and intellectual disability

We describe a boy with a de novo deletion of 15.67 Mb spanning 3q22.1q24. He has bilateral micropthalmia, ptosis, cleft palate, global developmental delay and brain, skeletal and cardiac abnormalities. In addition, he has bilateral inguinal hernia and his right kidney is absent. We compare his phenotype with seven other patients with overlapping and molecularly defined interstitial 3q deletions. This patient has some phenotypic features that are not shared by the other patients. More cases with smaller deletions defined by high resolution aCGH will enable better genotype–phenotype correlations and prioritizing of candidate genes for the identification of pathways and disease mechanisms.     

Chromosome 17p13.3 deletion syndrome: aCGH characterization,prenatal findings and diagnosis,and literature review

We report a molecular cytogenetic characterization of 17p13.3 deletion syndrome by array comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH) and quantitative polymerase chain reaction (qPCR) in a fetus with lissencephaly, corpus callosum dysgenesis, ventriculomegaly, microcephaly, intrauterine growth restriction (IUGR), polyhydramnios and single umbilical artery. aCGH analysis revealed a 3.17-Mb deletion at 17p13.3, or arr [hg19] 17p13.3 (0–3,165,530)×1. The qPCR assays revealed a maternal origin of the deletion. Metaphase FISH analysis detected the absence of the LIS1 probe signal on the aberrant chromosome 17. The karyotype was 46,XX,del(17)(p13.3). We review the literature of chromosome 17p13.3 deletion syndrome with prenatal findings and diagnosis, and suggest that prenatal ultrasound detection of central nervous system anomalies such as lissencephaly, corpus callosum dysgenesis/agenesis, ventriculomegaly and microcephaly associated with IUGR, polyhydramnios, congenital heart defects, abdominal wall defects and renal abnormalities should include a differential diagnosis of chromosome 17p13.3 deletion syndrome.     

A novel TNNI2 mutation causes Freeman–Sheldon syndrome in a Chinese family with an affected adult with only facial contractures

Distal arthrogryposes (DAs), a clinically and genetically heterogeneous group of disorders characterized by congenital contractures with predominant involvement of the hands and feet, can be classified into at least 12 different forms. These autosomal dominant disorders are of variable expressivity and reduced penetrance. Mutations in sarcomeric protein genes, including troponin I2 (TNNI2), troponin T3 (TNNT3), tropomyosin 2 (TPM2), embryonic myosin heavy chain 3 (MYH3), and myosin binding protein C1 (MYBPC1), have been identified in distal arthrogryposis type 1 (DA1, MIM 108120), type 2B (DA2B, MIM 601680) and type 2A (DA2A)/Freeman–Sheldon syndrome (FSS, MIM 193700). However, mutations causing FSS have only been reported in MYH3. Herein we describe a Chinese DA family whose members meet classical strict criteria for FSS, as well as one member of the family who has isolated facial features consistent with FSS. No disease-causing mutation was found in MYH3. Segregation of microsatellite markers flanking the TNNI2 and TNNT3 genes at 11p15.5 was compatible with linkage. Subsequent sequencing of TNNI2 revealed a novel mutation, c.A493T (p.I165F), located in the C-terminal region, which is critical for proper protein function. This mutation was found to cosegregate with the FSS phenotype in this family, and assessment using SIFT and PolyPhen-2 predicted a damaging effect. To the best of our knowledge, we report the first TNNI2 mutation in classical FSS and describe an atypical adult FSS case with only facial contractures resulting from somatic mosaicism. We infer that DA1, DA2B and FSS represent a phenotypic continuum of the same disorder and provide further genetic evidence for this hypothesis.     

Massive expansions of Dscam splicing diversity via staggered homologous recombination during arthropod evolution

The arthropod Down syndrome cell adhesion molecule (Dscam) gene can generate tens of thousands of protein isoforms via combinatorial splicing of numerous alternative exons encoding immunoglobulin variable domains organized into three clusters referred to as the exon 4, 6, and 9 clusters. Dscam protein diversity is important for nervous system development and immune functions. We have performed extensive phylogenetic analyses of Dscam from 20 arthropods (each containing between 46 and 96 alternative exons) to reconstruct the detailed history of exon duplication and loss events that built this remarkable system over 450 million years of evolution. Whereas the structure of the exon 4 cluster is ancient, the exon 6 and 9 clusters have undergone massive, independent expansions in each insect lineage. An analysis of nearly 2000 duplicated exons enabled detailed reconstruction of the timing, location, and boundaries of these duplication events. These data clearly show that new Dscam exons have arisen continuously throughout arthropod evolution and that this process is still occurring in the exon 6 and 9 clusters. Recently duplicated regions display boundaries corresponding to a single exon and the adjacent intron. The boundaries, homology, location, clustering, and relative frequencies of these duplication events strongly suggest that staggered homologous recombination is the major mechanism by which new Dscam exons evolve. These data provide a remarkably detailed picture of how complex gene structure evolves and reveal the molecular mechanism behind this process.     

Genetic analysis of TMPRSS3 gene in the Korean population with autosomal recessive nonsyndromic hearing loss

The TMPRSS3 gene (DFNB8/10), which encodes a transmembrane serine protease, is a common hearing loss gene in several populations. Accurate functions of TMPRSS3 in the hearing pathway are still unknown, but TMPRSS3 has been reported to play a crucial role in inner ear development or maintenance. To date, 16 pathogenic mutations have been identified in many countries, but no mutational studies of the TMPRSS3 gene have been conducted in the Korean hearing loss population. In this study, we performed genetic analysis of TMPRSS3 in 40 unrelated Korean patients with autosomal recessive hearing loss to identify the aspect and frequency of TMPRSS3 gene mutations in the Korean population. A total of 22 variations were detected, including a novel variant (p.V291L) and a previously reported pathogenic mutation (p.A306T). The p.A306T mutation which has been detected in only compound heterozygous state in previous studies was identified in homozygous state for the first time in this study. Moreover, the clinical evaluation identified bilateral dilated vestibules in the patient with p.A306T mutation, and it suggested that p.A306T mutation of the TMPRSS3 gene might be associated with vestibular anomalies. In conclusion, this study investigated that only 2.5% of patients with autosomal recessive hearing loss were related to TMPRSS3 mutations suggesting low prevalence of TMPRSS3 gene in Korean hearing loss population. Also, it will provide the information of genotype–phenotype correlation to understand definite role of TMPRSS3 in the auditory system.     

Further delineation of novel 1p36 rearrangements by array-CGH analysis: Narrowing the breakpoints and clarifying the "extended" phenotype

High resolution oligonucleotide array Comparative Genome Hybridization technology (array-CGH) has greatly assisted the recognition of the 1p36 contiguous gene deletion syndrome. The 1p36 deletion syndrome is considered to be one of the most common subtelomeric microdeletion syndromes and has an incidence of ~1 in 5000 live births, while respectively the "pure" 1p36 microduplication has not been reported so far. We present seven new patients who were referred for genetic evaluation due to Developmental Delay (DD), Mental Retardation (MR), and distinct dysmorphic features. They all had a wide phenotypic spectrum. In all cases previous standard karyotypes were negative. Array-CGH analysis revealed five patients with interstitial 1p36 microdeletion (four de novo and one maternal) and two patients with de novo reciprocal duplication of different sizes. These were the first reported "pure" 1p36 microduplication cases so far. Three of our patients carrying the 1p36 microdeletion syndrome were also found to have additional pathogenetic aberrations. These findings (del 3q27.1; del 4q21.22-q22.1; del 16p13.3; dup 21q21.2-q21.3; del Xp22.12) might contribute to the patients' severe phenotype, acting as additional modifiers of their clinical manifestations. We review and compare the clinical and array-CGH findings of our patients to previously reported cases with the aim of clearly delineating more accurate genotype-phenotype correlations for the 1p36 syndrome that could allow for a more precise prognosis.     

Mutation analyses in pedigrees and sporadic cases of ethnic Han Chinese Kallmann syndrome patients

Kallmann syndrome, a form of idiopathic hypogonadotropic hypogonadism, is characterized by developmental abnormalities of the reproductive system and abnormal olfaction. Despite association of certain genes with idiopathic hypogonadotropic hypogonadism, the genetic inheritance and expression are complex and incompletely known. In the present study, seven Kallmann syndrome pedigrees in an ethnic Han Chinese population were screened for genetic mutations. The exons and intron–exon boundaries of 19 idiopathic hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism)-related genes in seven Chinese Kallmann syndrome pedigrees were sequenced. Detected mutations were also tested in 70 sporadic Kallmann syndrome cases and 200 Chinese healthy controls. In pedigrees 1, 2, and 7, the secondary sex characteristics were poorly developed and the patients’ sense of smell was severely or completely lost. We detected a genetic mutation in five of the seven pedigrees: homozygous KAL1 p.R191ter (pedigree 1); homozygous KAL1 p.C13ter (pedigree 2; a novel mutation); heterozygous FGFR1 p.R250W (pedigree 3); and homozygous PROKR2 p.Y113H (pedigrees 4 and 5). No genetic change of the assayed genes was detected in pedigrees 6 and 7. Among the 70 sporadic cases, we detected one homozygous and one heterozygous PROKR2 p.Y113H mutation. This mutation was also detected heterozygously in 2/200 normal controls and its pathogenicity is likely questionable. The genetics and genotype–phenotype relationships in Kallmann syndrome are complicated. Classical monogenic inheritance does not explain the full range of genetic inheritance of Kallmann syndrome patients. Because of stochastic nature of genetic mutations, exome analyses of Kallmann syndrome patients may provide novel insights.