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.     

Identification of a patient with intellectual disability and de novo 3.7 Mb deletion supports the existence of a novel microdeletion syndrome in 2p14–p15

Microdeletions spanning 2p14–p15 have recently been described in two patients with developmental and speech delay and intellectual disability but no congenital malformations or severe facial dysmorphism. We report a 4-year-old boy with a de novo 3.7 Mb long deletion encompassing the region deleted in the previous cases. The patient had clinical features partly consistent with the published cases including intellectual disability, absent speech, microcephaly, long face, bulbous nasal tip and thin upper lip, but his overall clinical picture was more severe compared to the published patients. The identification of this additional patient and a detailed analysis of deletions identified in various patient cohorts and in normal individuals support the existence of a new rare microdeletion syndrome in 2p14–p15. Its critical region is in the vicinity of but clearly separate from the minimal region deleted in the well established 2p15–p16.1 microdeletion syndrome. A thorough comparison of the deletions and phenotypes indicates that multiple genes located in this region may be involved in intellectual functioning, and that some patients may show composite and more complex phenotypes due to deletions spanning both critical regions.     

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.     

Chromosome 19p13.3 deletion in a child with Peutz-Jeghers syndrome, congenital heart defect, high myopia, learning difficulties and dysmorphic features: Clinical and molecular characterization of a new contiguous gene syndrome

The Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome characterized by mucocutaneous pigmentation, gastrointestinal polyps and the increased risk of multiple cancers. The causative point mutation in the STK11 gene of most patients accounts for about 30% of the cases of partial and complete gene deletion. This is a report on a girl with PJS features, learning difficulties, dysmorphic features and cardiac malformation, bearing a de novo 1.1 Mb deletion at 19p13.3. This deletion encompasses at least 47 genes, including STK11. This is the first report on 19p13.3 deletion associated with a PJS phenotype, as well as other atypical manifestations, thereby implying a new contiguous gene syndrome.     

Genotype-phenotype correlation of a 5q22.3 deletion associated with craniofacial and limb defects

We describe here a newborn with a de novo 22.6 Mb interstitial deletion of chromosome 5q22.3. The clinical findings included brachycephaly, a high forehead, hypertelorism with prominent eyes, low-set ears, clenched hands, club feet, a prominent coccyx with hair, ambiguous genitalia, inguinal hernia, heart defect and severe failure to thrive. This case had a more severe phenotype, compared with the previous reports of interstitial 5q syndrome. High resolution multicolor banding and array comparative genomic hybridization (array CGH) analysis delineated the breakpoints at 5q22.3 and 5q31.2. There were no obvious candidate genes for the specific correlation with the phenotypes except a PITX1 gene associated with the phenotype of club feet. Further cumulative data based on the molecular approach are needed to establish the genotype-phenotype correlation and to understand the role and influence of the genes in the interstitial 5q syndrome.     

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.     

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.     

Novel chromosomal translocation t(11;9)(p15;p23) involving deletion and duplication of 9p in a girl associated with autism and mental retardation

We describe a 5-year-old girl presented with autism and mental retardation features. Conventional karyotyping revealed a novel unidirectional translocation t(11;9)(p15;p23). HumanCytoSNP-12 Chip analysis identified a 13 Mb deletion from 9p24.3 to 9p23 and a 12.5Mb duplication from 9p23 to 9p21.2. The karyotype was described as 45,XX,psu dic(11; 9)(p15;p23), which was reported for the first time here. The deleted region, extending from 9p24.3 to 9p23, overlaps with the candidate region for monosomy 9p syndrome and contains a potential autism spectrum disorders (ASD) locus. The duplication region extending from 9p23 to 9p21.2 was previously identified as a critical region for the 9p duplication syndrome. These results suggested that the apparently balanced de novo translocations could produce cryptic deletions or duplications, and the precise mapping of the abnormal area may improve clinical management.     

A patient with partial trisomy 21 and 7q deletion expresses mild Down syndrome phenotype

Backround

Down syndrome (DS) is the most common aneuploidy in live-born individuals and it is well recognized with various phenotypic expressions. Although an extra chromosome 21 is the genetic cause for DS, specific phenotypic features may result from the duplication of smaller regions of the chromosome and more studies need to define genotypic and phenotypic correlations.

Case report

We report on a 26 year old male with partial trisomy 21 presenting mild clinical symptoms relative to DS including borderline intellectual disability. In particular, the face and the presence of hypotonia and keratoconus were suggestive for the DS although the condition remained unnoticed until his adult age array comparative genomic hybridization (aCGH) revealed a 10.1 Mb duplication in 21q22.13q22.3 and a small deletion of 2.2 Mb on chromosomal band 7q36 arising from a paternal translocation t(7;21). The 21q duplication encompasses the gene DYRK1.

Conclusion

Our data support the evidence of specific regions on distal 21q whose duplication results in phenotypes recalling the typical DS face. Although the duplication region contains DYRK1, which has previously been implicated in the causation of DS, our patient has a borderline IQ confirming that their duplication is not sufficient to cause the full DS phenotype.     

A 1.5 Mb terminal deletion of 12p associated with autism spectrum disorder

We report a patient with a terminal 12p deletion associated with autism spectrum disorder (ASD). This 12p13.33 deletion is 1.5 Mb in size and encompasses 13 genes (B4GALNT3, CCDC77, ERC1, FBXL14, IQSEC3, KDM5A, LINC00942, LOC574538, NINJ2, RAD52, SLC6A12, SLC6A13 and WNK1). All previous cases reported with partial monosomy of 12p13.33 are associated with neurodevelopmental delay, and we suggest that ERC1, which encodes a regulator of neurotransmitter release, is the best gene candidate contributing to this phenotype as well as to the ASD of our patient.     

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.     

Microduplications in 22q11.2 and 8q22.1 associated with mild mental retardation and generalized overgrowth

The 22q11.2 microduplication is a genomic disorder, characterized from a variable phenotype ranging from different defects to normality. The most common microduplication of 22q11.2 is 3 Mb in size, but there are also cases reported with atypical duplications between 0.8 Mb and 6 Mb.     

Contribution of SNP arrays in diagnosis of deletion 2p11.2-p12

Deletions of the short arm of chromosome 2 are exceedingly rare, having been reported in few patients. Furthermore most cases with deletion in 2p11.2-p12 have been studied using standard karyotype and so it is not possible to delineate the precise size of deletions.Here, we describe a 9-year-old girl with a 9.4 Mb de novo interstitial deletion of region 2p11.2-p12 identified by SNP array analysis.The deleted region encompasses over 40 known genes, including LRRTM1, CTNNA2 and REEP1, haploinsufficiency of which could explain some clinical features of this patient such as mental retardation, speech delay and gait abnormalities.A comparison of our case with previously reported patients who present deletions in 2p11.2-p12 was carried out.Our case adds new information to the deletion of 2p11.2-p12, improving the knowledge on this rearrangement.     

Different matrix attachment regions flanking a transgene effectively enhance gene expression in stably transfected Chinese hamster ovary cells

We describe a female patient with developmental delay, dysmorphic features and multiple congenital anomalies who presented a normal G-banded karyotype at the 550-band resolution. Array and multiplex-ligation probe amplification (MLPA) techniques identified an unexpected large unbalanced genomic aberration: a 17.6Mb deletion of 9p associated to a 14.8 Mb duplication of 20p. The deleted 9p genes, especially CER1 and FREM1, seem to be more relevant to the phenotype than the duplicated 20p genes. This study also shows the relevance of using molecular techniques to make an accurate diagnosis in patients with dysmorphic features and multiple anomalies suggestive of chromosome aberration, even if on G-banding their karyotype appears to be normal. Fluorescence in situ hybridization (FISH) was necessary to identify a masked balanced translocation in the patient's mother, indicating the importance of associating cytogenetic and molecular techniques in clinical genetics, given the implications for patient management and genetic counseling.     

Complex rearrangement involving 9p deletion and duplication in a syndromic patient: genotype/phenotype correlation and review of the literature

We describe a 7-year-old boy with a complex rearrangement involving the whole short arm of chromosome 9 defined by means of molecular cytogenetic techniques. The rearrangement is characterized by a 18.3 Mb terminal deletion associated with the inverted duplication of the adjacent 21,5 Mb region. The patient shows developmental delay, psychomotor retardation, hypotonia. Other typical features of 9p deletion (genital disorders, midface hypoplasia, long philtrum) and of the 9p duplication (brachycephaly, down slanting palpebral fissures and bulbous nasal tip) are present. Interestingly, he does not show trigonocephaly that is the most prominent dysmorphism associated with the deletion of the short arm of chromosome 9. Patient's phenotype and the underlying flanking opposite 9p imbalances are compared with that of reported patients and the proposed critical regions for 9p deletion and 9p duplication syndromes.     

Allelic variants of DYX1C1 are not associated with dyslexia in India

Dyslexia is a hereditary neurological disorder that manifests as an unexpected difficulty in learning to read despite adequate intelligence, education, and normal senses. The prevalence of dyslexia ranges from 3 to 15% of the school aged children. Many genetic studies indicated that loci on 6p21.3, 15q15-21, and 18p11.2 have been identified as promising candidate gene regions for dyslexia. Recently, it has been suggested that allelic variants of gene, DYX1C1 influence dyslexia. In the present study, exon 2 and 10 of DYX1C1 has been analyzed to verify whether these single nucleotide polymorphisms (SNPs) influence dyslexia, in our population. Our study identified 4 SNPs however, none of these SNPS were found to be significantly associated with dyslexia suggesting DYX1C1 allelic variants are not associated with dyslexia.     

Mowat–Wilson syndrome detected by using high resolution microarray

Individuals with Mowat–Wilson syndrome (MWS; OMIM#235730) have characteristic facial features, a variety of congenital anomalies such as Hirschsprung disease, and intellectual disabilities caused by mutation or deletion of ZEB2 gene. This deletion or cytogenetic abnormality has been reported primarily from Europe, Australia and the United States, but not in Korea. Here we report a patient with characteristic facial features of MWS, developmental delay and spasticity. High resolution microarray analysis revealed 0.9 Mb deletion of 2q22.3 involving two genes: ZEB2 and GTDC1. This case shows the important role of high resolution microarray in patients with unexplained psychomotor retardation and/or facial dysmorphism. Knowledge about the most striking clinical signs and implementation of effective molecular tests like microarray could significantly increase the detection rate of new cases of MWS in Korea. This is the first reported case of MWS in Korea.     

16q22.1 microdeletion detected by array-CGH in a family with mental retardation and lobular breast cancer

We describe the case of a boy with psychomotor delay and dysmorphic features, with a germline 16q22.1 microdeletion identified by array-CGH. The deletion spans 0.24Mb and encompasses three genes (ZFP90, CDH3 and CDH1). The deletion has been demonstrated to be inherited from his mother who was affected by lobular breast cancer (LBC) without any other apparently phenotypic features. We suppose that the microdeletion, in particular ZFP90 which is cerebrally expressed, is causative for the boy's phenotype. Mental retardation in the affected boy can recognize several mechanisms such as variable expressivity, non-penetrance, multifactorial/polygenic inheritance, recessive inheritance, a second rearrangement event and epigenetics. Furthermore, we suggest that the deletion of the CDH1, a tumor suppressor gene, involved in hereditary diffuse gastric cancer (HDGC) and LBC predisposed the mother to the carcinoma.