Hereditary hearing impairment is one of the major and common birth defects in Chinese population. Non-syndromic sensorineural hearing loss (NSHL) is the most common types of hereditary hearing impairment. Genotypically and phenotypically NSHL is extremely heterogenous and follow either autosomal dominant or autosomal recessive or X-linked mode of inheritance. Presently, 127 genes have been identified to be associated with both syndromic and (NSHL). Here, we studied a Chinese family with moderate and profound hearing impairment. The proband is a 30-year old Chinese man. The proband was born with normal hearing and at the age of 5-years, the proband was first noticed with hearing impairment. Gradually and progressively the proband was presented with loss of hearing in his both right and left ears at the age of 30 years. The clinical symptoms, age of onset or progression to loss of hearing was similar in both the proband and his younger brother. The proband’s parents are phenotypically normal and non-consanguineous. Clinical diagnosis of the proband and his younger brother has been done by classical pure tone audiogram (PTA). Computed Tomography (CT) found no abnormality in bilateral external ear, middle ear and inner ear. Targeted next generation sequencing was performed with a panel of 127 genes reported to be associated with hereditary hearing impairment. A novel homozygous single nucleotide deletion (c.427delT) in exon 4 of ILDR1 gene has been identified in proband and in his younger brother. Sanger sequencing confirmed that proband’s father and mother are carrying this mutation in a heterozygous manner. This mutation has not been identified in 100 normal healthy control individuals. This mutation (c.427delT) causes frameshift (p.Tyr143Ilefs∗19) which leads to the formation of a truncated ILDR1 protein of 162 amino acids instead of the wild type ILDR1 protein of 546 amino acids. ILDR1 associated hereditary hearing impairment is very rare and this is the first report of identifying a loss-of-function mutation in ILDR1 gene associated with hereditary hearing impairment in Chinese population. Our present study also emphasized the significance of rapid, accurate and cost-effective screening for the patient with hereditary hearing impairment by targeted next generation sequencing.

Down syndrome caused by meiotic nondisjunction of chromosome 21 in humans, is well known to be associated with advanced maternal age, but success in identifying and understanding other risk factors has been limited. Recently published work in a U.S. population suggested intriguing interactions between the maternal age effect and altered recombination patterns during meiosis, but some of the results were counter-intuitive. We have tested these hypotheses in a population sample from India, and found that essentially all of the results of the U.S. study are replicated even in our ethnically very different population. We examined meiotic recombination patterns in a total of 138 families from the eastern part of India, each with a single free trisomy 21 child. We genotyped each family with a set of STR markers using PCR and characterized the stage of origin of nondisjunction and the recombination pattern of maternal chromosome 21 during oogenesis. Our sample contains 107 maternal meiosis I errors and 31 maternal meiosis II errors and we subsequently stratified them with respect to maternal age and the number of detectable crossover events. We observed an association between meiosis I nondisjuncion and recombination in the telomeric 5.1 Mb of chromosome 21. By contrast, in meiosis II cases we observed preferential peri-centromeric exchanges covering the proximal 5.7 Mb region, with interaction between maternal age and the location of the crossover. Overall reduction of recombination irrespective of maternal age is also evident in meiosis I cases. Our findings are very consistent with previously reported data in a U.S. population and our results are the first independent confirmation of those previous reports. This not only provides much needed confirmation of previous results, but it suggests that the genetic etiology underlying the occurrence of trisomy 21 may be similar across human populations.

Tridentate/tetradentate Schiff base ligands L(1) and L(2), derived from the condensation of o-vanillin or pyridine-2-aldehyde with N,N-dimethylethylenediammine, react with nickel acetate or perchlorate salt and azide, cyanate, or thiocyanate to give rise to a series of dinuclear complexes of formulas [Ni(L(1))(micro(1,1)-N(3))Ni(L(1))(N(3))(OH(2))].H(2)O (1), [[Ni(L(1))(micro(1,1)-NCS)Ni(L(1))(NCS)(OH(2))][Ni(L(1))(micro-CH(3)COO)Ni(L(1))( NCS) (OH(2))]] (2) [[2A][2B]], [Ni(L(1))(micro(1,1)-NCO)Ni(L(1))(NCO)(OH(2))].H(2)O (3), and [Ni(L(2)-OMe)(micro(1,1)-N(3))(N(3))](2) (4), where L(1) = Me(2)N(CH(2))(2)NCHC(6)H(3)(O(-))(OCH(3)) and L(2) = Me(2)N(CH(2))(2)NCHC(6)H(3)N. We have characterized these complexes by analytical, spectroscopic, and variable-temperature magnetic susceptibility measurements. The coordination geometry around all of the Ni(II) centers is a distorted octahedron with bridging azide, thiocyanate/acetate, or cyanate in a micro(1,1) mode and micro(2)-phenolate oxygen ion for 1-3, respectively, or with a double-bridging azide for 4. The magnetic properties of the complexes were studied by magnetic susceptibility (chi(M)) versus temperature measurements. The chi(M) nus T plot reveals that compounds 1 and 4 are strongly ferromagnetically coupled, 3 shows a weak ferromagnetic behavior, and 2 is very weakly antiferromagnetically coupled.

Flat, quantum dot like arrays of closely spaced, electron rich metal centres are seen as attractive subunits for device capability at the molecular level. Mn(II)9 grids, formed by self-assembly processes using 'tritopic' pyridine-2,6-dihydrazone ligands, provide easy and pre-programmable routes to such systems, and have been shown to exhibit a number of potentially useful physical properties, which could be utilized to generate bi-stable molecular based states. Their ability to form surface monolayers, which can be mapped by STM techniques, bodes well for their possible integration into nanometer scale electronic components of the future. This report highlights some new Mn(II)9 grids, with functionalized ligand sites, that may provide suitable anchor points to surfaces and also be potential donor sites capable of further grid elaboration. Structures, magnetic properties, electrochemical properties, surface studies on HOPG (highly ordered pyrolytic graphite), including the imaging of individual metal ion sites in the grid using CITS (current imaging tunneling spectroscopy) are discussed, in addition to an analysis of the photophysics of a stable mixed oxidation state [Mn(III)4Mn(II)5] grid. The grid physical properties as a whole are assessed in the light of reasonable approaches to the use of such molecules as nanometer scale devices.

Polymetallic, highly organized molecular architectures can be created by "bottom-up" self-assembly methods using ligands with appropriately programmed coordination information. Ligands based on 2,6-picolyldihydrazone (tritopic and pentatopic) and 3,6-pyridazinedihydrazone (tetratopic) cores, with tridentate coordination pockets, are highly specific and lead to the efficient self-assembly of square [3 x 3] Mn9, [4 x 4] Mn16, and [5 x 5] Mn25 nanoscale grids. Subtle changes in the tritopic ligand composition to include bulky end groups can lead to a rectangular 3 x [1 x 3] Mn9 grid, while changing the central pyridazine to a more sterically demanding pyrazole leads to simple dinuclear copper complexes, despite the potential for binding four metal ions. The creation of all bidentate sites in a tetratopic pyridazine ligand leads to a dramatically different spiral Mn4 strand. Single-crystal X-ray structural data show metallic connectivity through both mu-O and mu-NN bridges, which leads to dominant intramolecular antiferromagnetic spin exchange in all cases. Surface depositions of the Mn9, Mn16, and Mn25 square grid molecules on graphite (HOPG) have been examined using STM/CITS imagery (scanning tunneling microscopy/current imaging tunneling spectroscopy), where tunneling through the metal d-orbital-based HOMO levels reveals the metal ion positions. CITS imagery of the grids clearly shows the presence of 9, 16, and 25 manganese ions in the expected square grid arrangements, highlighting the importance and power of this technique in establishing the molecular nature of the surface adsorbed species. Nanoscale, electronically functional, polymetallic assemblies of this sort, created by such a bottom-up synthetic approach, constitute important components for advanced molecule-based materials.

A tridentate Schiff base carboxylate ligand, derived from the condensation of pyridine 2-carboxaldehyde with anthranilic acid, reacts with copper trifluoroacetate salt to give rise to the helical chain complex [Cu(C(13)H(9)N(2)O(2))(F(3)CCO(2))](n)() (1) and with copper nitrate to give rise to the tetranuclear complex [[Cu(4)(C(13)H(9)N(2)O(2))(4)(H(2)O)(4)].3.5NO(3).0.5N(3)] (2) with the addition of azide salt. The structures of these complexes have been solved by X-ray crystallography. The Cu(II) ions are in a distorted square-pyramidal environment in complex 1. They are sequentially bridged by carboxylate groups in the syn-anti conformation, resulting in the formation of an infinite helix like chain along the crystallographic c-axis. The crystal structure of complex 2 consists of tetranuclear [Cu(4)(L)(4)(H(2)O)(4)](4+) (L = C(13)H(9)N(2)O(2)(-)) cations and isolated NO(3)(-) and N(3)(-) anions in the ratio 1:3.5:0.5, respectively, involving bridging carboxylate groups in the syn-anti conformation. For 1 the carboxylato-Cu(II) coordination is apical-basal, while for 2 it is basal-basal. From the magnetic susceptibility measurements the complex 1 is found to exhibit very weak antiferromagnetic interaction whereas a weak ferromagnetic coupling has been established for complex 2. The magnetic behavior can be satisfactorily explained on the basis of the structural data for these and related complexes.

Meckel syndrome (MKS) is a pre-or perinatal multisystemic ciliopathic lethal disorder with an autosomal recessive mode of inheritance. Meckel syndrome is usually manifested with meningo-occipital encephalocele, polycystic kidney dysplasia, postaxial polydactyly and hepatobiliary ductal plate malformation. Germline variants in CEP290 cause MKS4. In this study, we investigated a 35-years-old Chinese female who was 17+1 weeks pregnant. She had a history of adverse pregnancy of having foetus with multiple malformations. We performed ultrasonography and identified the foetus with occipital meningoencephalocele and enlarged cystic dysplastic kidneys. So, she decided to terminate her pregnancy and further genetic molecular analysis was performed. We identified the aborted foetus without postaxial polydactyly. Histological examination of foetal kidney showed cysts in kidney and thinning of the renal cortex with glomerular atrophy. Whole exome sequencing identified a novel homozygous variant (c.2144T>G; p.L715 * ) in exon 21 of the CEP290 in the foetus. Sanger sequencing confirmed that both the parents of the foetus were carrying this variant in a heterozygous state. This variant was not identified in two elder sisters of the foetus as well as in the 100 healthy individuals. Western blot analysis showed that this variant leads to the formation of truncated CEP290 protein with the molecular weight of 84 KD compared with the wild-type CEP290 protein of 290 KD. Hence, it is a loss-of-function variant.We also found that the mutant cilium appears longer in length than the wild-type cilium. Our present study reported the first variant of CEP290 associated with MKS4 in Chinese population.

Hypertriglyceridaemia is a very rare disorder caused by the mutations of LPL gene, with an autosomal recessive mode of inheritance. Here, we identified two unrelated Chinese patients manifested with severe hypertriglyceridaemia and acute pancreatitis. The clinical symptoms of proband 1 are more severe than proband 2. Whole exome sequencing and Sanger sequencing were performed. Functional analysis of the identified mutations has been done. Whole exome sequencing identified two pairs of variants in LPL gene in the proband 1 (c.162C>A and c.1322+1G>A) and proband 2 (c.835C>G and c.1322+1G>A). The substitution (c.162C>A) leads to the formation of a truncated (p.Cys54*) LPL protein. The substitution (c.835C>G) leads to the replacement of leucine to valine (p.Leu279Val). The splice donor site mutation (c.1322+1G>A) leads to the formation of alternative transcripts with the loss of 134 bp in exon 8 of the LPL gene. The proband 1 and his younger son also harbouring a heterozygous variant (c.553G>T; p.Gly185Cys) in APOA5 gene. The relative expression level of the mutated LPL mRNA (c.162C>A, c.835C>G and c.1322+1G>A) showed significant differences compared to wild-type LPL mRNA, suggesting that all these three mutations affect the transcription of LPL mRNA. These three mutations (c.162C>A, c.835C>G and c.1322+1G>A)showed noticeably decreased LPL activity in cell culture medium but not in cell lysates.Here, we identified three mutations in LPL gene which causes severe hypertriglyceridaemia with acute pancreatitis in Chinese patients. We also described the significance of whole exome sequencing for identifying the candidate gene and disease-causing mutation in patients with severe hypertriglyceridaemia and acute pancreatitis.