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PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

Background Mutations in the STXBP1 gene (MUNC18-1) were first described to cause Ohtahara syndrome (Early infantile epileptic encephalopathy, EIEE)12–14 characterized by very early infantile epileptic encephalopathy with frequent tonic spasms and a suppression-burst pattern on electroencephalogram. In the following years a wider phenotype was recognized having milder forms of epilepsies. All patients showed also intellectual disability and movement disorders. Methods Here, we present three female patients with an ataxia-tremor-retardation syndrome caused by a de novo STXBP1 mutation. Two of the girls were diagnosed through next-generation-sequencing as mutations in STXBP1 were not suspected. The third patient was diagnosed by targeted genetic testing due to its clinical features strikingly similar to the first two girls. Results The characteristic feature of our three patients is the lack of epilepsy which is in contrast to the majority of the patients with STXBP1 mutation. Conclusion Hence, epilepsy is not a mandatory feature of patients with a STXBP1 mutation.

Expression of the fusion genes is considered to be an important mechanism of tumorigenesis. However it is hardly ever discussed in relation to the neurodevelopmental disorders. Here we report on an 18-years-old female patient with 13.1 kb deletion of 8q24.3 fusing the 5′-portion of SCRIB with the 3′-portion of PUF60 and presenting with borderline intellectual disability, eye coloboma, short stature, scoliosis, heart defects and interestingly postnatal megalencephaly, in contrast to microcephaly, which is usually associated with 8q24.3 deletion (Verheij syndrome). Using next generation sequencing we mapped the breakpoints at nucleotide resolution and showed that the deletion preserved the reading frame. In contrast to the laborious techniques previously used for the precise mapping of deletion breakpoints, our approach identified an accurate interval very rapidly. We demonstrated the expression of the PUF60-SCRIB fusion gene in patient's cells and suggest that the fusion transcript might be a cause of the atypical clinical presentation.

Exome sequencing identified compound heterozygous mutations in the recently discovered mitochondrial methionyl-tRNA formyltransferase (MTFMT) gene in two sisters with mild Leigh syndrome and combined respiratory chain deficiency. The mutations lead to undetectable levels of the MTFMT protein. Blue native polyacrylamide gel electrophoresis showed decreased complexes I and IV, and additional products stained with complex V antibodies, however the overall steady state level of mt-tRNA(Met) was normal. Our data illustrate that exome sequencing is an excellent diagnostic tool, and its value in clinical medicine is enormous, however it can only be optimally exploited if combined with detailed phenotyping and functional studies.

Recent studies have shown that autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to believe that the number of underlying gene defects goes into the thousands. To date, however, only four genes have been implicated in nonsyndromic ARMR (NS-ARMR): PRSS12 (neurotrypsin), CRBN (cereblon), CC2D1A, and GRIK2. As part of an ongoing systematic study aiming to identify ARMR genes, we investigated a large consanguineous family comprising seven patients with nonsyndromic ARMR in four sibships. Genome-wide SNP typing enabled us to map the relevant genetic defect to a 4.6 Mbp interval on chromosome 8. Haplotype analyses and copy-number studies led to the identification of a homozygous deletion partly removing TUSC3 (N33) in all patients. All obligate carriers of this family were heterozygous, but none of 192 unrelated healthy individuals from the same population carried this deletion. We excluded other disease-causing mutations in the coding regions of all genes within the linkage interval by sequencing; moreover, we verified the complete absence of a functional TUSC3 transcript in all patients through RT-PCR. TUSC3 is thought to encode a subunit of the endoplasmic reticulum-bound oligosaccharyltransferase complex that catalyzes a pivotal step in the protein N-glycosylation process. Our data suggest that in contrast to other genetic defects of glycosylation, inactivation of TUSC3 causes nonsyndromic MR, a conclusion that is supported by a separate report in this issue of AJHG. TUSC3 is only the fifth gene implicated in NS-ARMR and the first for which mutations have been reported in more than one family.

Nonsyndromic mental retardation is one of the most important unresolved problems in genetic health care. Autosomal forms are far more common than X-linked forms, but, in contrast to the latter, they are still largely unexplored. Here, we report a complex mutation in the ionotropic glutamate receptor 6 gene (GRIK2, also called "GLUR6") that cosegregates with moderate-to-severe nonsyndromic autosomal recessive mental retardation in a large, consanguineous Iranian family. The predicted gene product lacks the first ligand-binding domain, the adjacent transmembrane domain, and the putative pore loop, suggesting a complete loss of function of the GLU(K6) protein, which is supported by electrophysiological data. This finding provides the first proof that GLU(K6) is indispensable for higher brain functions in humans, and future studies of this and other ionotropic kainate receptors will shed more light on the pathophysiology of mental retardation.

The Mossbauer parameters are reported on twenty-five tetra-, penta- and hexacoordinated organotin compounds of the general types RSn(CH 2 CH 2 CH 2 ) 3 N (R=Cl, Me), RR'Sn(CH 2 CH 2 CH 2 ) 2 E (R=Cl, Me; R′=Cl, Me; E=NMe, O), Me 2 ClSnCH 2 CH 2 CH 2 E (E=NMe 2 , PPhBu t , MeNCH 2 CH 2 N- (Me)CH 2 CH 2 CH 2 SnMe 2 Cl), RR′Sn[CH 2 CH 2 CH 2 N(Me)CH 2 ] 2 (R=R′=Cl, Br, I, SPh; R=Me, R′=Cl), {SSn[CH 2 CH 2 CH 2 N(Me)CH 2 ] 2 } 2 , Cl 2 Sn(CH 2 CH 2 CH 2 NMe 2 ) 2 , S(CH 2 CH 2 CH 2 SnMe 3-n )Cl n ) 2 ( n = 1,2), Et (3− n ) X n SnCH 2 CH 2 E (n = 0, E = P(O)(OEt)Ph, P(O)Bu 2 ; n = 1, X = Br, E = P(O)(OEt)Ph, P(O)Bu 2 ), Me 2 ClSnCH 2 CH 2 PPh 2 and Ph(O)P(CH 2 CH 2 SnClMe 2 ) 2 . Quadrupole splitting and η values calculated on the basis of the concept of partial quadrupole splittings are in agreement with the molecular structures concluded from X-ray measurements and NMR studies.

The synthesis of bis(organostannyl)ethanes of the types (Ph 2 XSnCH 2 ) 2 ( 1 , X = Ph; 2 , X = Cl; 3 , X = Br; 4 , X = I) and (Ph 2 XSnCH 2 ) 2 ( 5 , X = Br, 6 , X = I) is described. The compounds have been investigated by means of 1 H, 13 C and 119 Sn NMR spectroscopy. 2 reacts with HMPA, [Ph 3 P = N = PPh 3 ] + Cl − , and Ph 4 PBr, respectively, to give the 1/1 complexes (Ph 2 ClSnCH 2 ) 2 · HMPA ( 7 ), [Ph 2 ClSnCH 2 ) 2 · Cl] − [Ph 3 PNPPh 3 ] + ( 8 ), and [(Ph 2 ClSnCH 2 ) 2 · Br] − [Ph 4 P] + ( 9 ). The formation constant K a for 8 in CDCl 3 solution is 2260 M −1 . The structures of 7 and 8 have been determined by X-ray diffraction. That of 7 shows that the two tin atoms are pentacoordinate but are inequivalent as a result of having different coordination sphere; one tin atom is coordinated by the monodentate HMPA (SnO 2.255(3) A) whereas the other interacts with a bridging Cl (Sn(1); Cl(2) 3.000(1) A). In the anion of 8 , the bis(chlorodiphenylstannyl)ethane may be regarded as an unsymmetrical chelate ligand towards Cl(12) (Sn(1)-Cl(12) 2.83(1), Sn(2)-Cl(12) 2.70(1) A).

The synthesis of 1,1,6,6,11,11-hexamethyl-1,6,11-tristannacyclopentadecane is reported. Its complexing ability for halide ions (Cl − , Br − ) is discussed and compared with that of the corresponding twelve-membered ring compound.

The reaction of N,N -bis(diphenylphosphinomethyl)amino acid derivatives with [Rh(dien)Cl] 2 yields six-membered chelate-rhodium complexes, which in hydrogenation reactions achieve optical yields of about 30% of α-acetamidocinnamic acid derivatives, independently of the amino acid used. The synthesis of the pre-catalysts and NMR studies of the in situ preparation show complex formation corresponding to the various solvents used. In polar solvents active catalysts are formed.

The compound pentacarbonyl-5-t-butyl-5-aza-2,8-dithia-1-stannobicyclo-[3.3.01,5]octanechromium(0) was prepared in good yield by the reaction of 5-t-butyl-5-aza-2,8-dithia-1-stannobicyclo[3.3.01,5]octane with Cr(CO)6 in THF under UV-irradiation. The crystal and molecular structure was determined from three-dimensional X-ray data. The crystals are monoclinic, space group P21/c. The unit cell, with dimensions a 14.963(9), b 10.026(5), c 13.565(5)Å, β 114.68°(5), contains 4 molecules. The structure was solved by the Patterson-method. The full-matrix refinement with the 2734 independent reflexions gave a final R value of 0.034. The eight-membered ring adopts an asymmetric boat-boat conformation with a tin-nitrogen bond lenght of 2.40 Å; the tin-chromium bond length is 2.62 Å.

α-Aminoacids, their esters and sodium salts may be transformed by a modified Mannich-reaction into N -phosphinomethyl or N,N -bis(phosphinomethyl) derivatives. The sodium or triethylammonium salts of the chiral bisphosphines l -()- N,N -bis(diphenylphosphinomethyl)-alanine and -valine may be used as ligands to form enantioselective hydrogenation catalysts with rhodium complexes. The highest optical yield achieved was 29%.

In contrast to arsabenzenes the π-excess aromatic 1H-1,3-benzazarsoles can be alkylated at the arsenic atom as well as lithiated in positions 1 or 2 without addition of LiN(i-Pr)2 and t-BuLi to the AsC (4p-2p)π bond. Alkylations and acylations of the ambident 1-lithio derivatives and substitution reactions of the 2-lithiobenzazarosole are described and the 1H and 13C NMR data of the compounds obtained are given.

The synthesis and structure of pentacarbonylmetal(0) complexes of the types (C0) 5 MSn(XCH 2 CH 2 ) 2 E (M = Cr, Mo, W; X = O, S; E = NR, PPh, O, S) and (CO) 5 WSn(SCH 2 CH 2 ) 2 E · py (E = NMe, O, S) are reported. 119 Sn and 13 C NMR studies show the compounds with X = O and E = NR to be dimeric whereas the derivatives with X = S have been found to be monomeric. The π-acceptor behaviour of the ligands Sn(XCH 2 CH 2 ) 2 E is comparable to that of the phosphanes. The barriers to internal rotations about the nitrogencarbon bonds have been determined for the NBu t derivatives.

The 1 H and 13 C NMR data for some N -methyl-5,5-dialkyldiptychthiaazstannolidines are reported. The differing coupling constants of the proton signals of the two nonequivalent Sn-alkyl groups suggest apical/equatorial positions for these groups at the pentacoordinated tin atom. The observed intramolecular process is explained by a dissociation-inversion mechanism.

The compound PhP(CH2CH2S)2SnCr(CO)5. C5H5N crystallizes in the triclinic space group P 1 with two molecules in a unit cell of dimensions a 10.654(2), b 10.146(3), c 12.448(3) A, α 85.31(2), β 79.66(2), γ 65.53(2)°, V 1204.8 A3. The structure was solved by the Patterson method. The full matrix refinement with the 4456 observed reflections gave a final R value of 0.034. The tin atom is pentacoordinated by 2S, Cr, N and P. The SnCr distance is 2.618 A, and the SnN and SnP donor-acceptor interactions are 2.514 and 2.756 A, respectively. The eight-membered ring adopts a boat-chair conformation.

The reactions of o -arsinophenoles with some carboxylic acid derivatives were studied. With imidoyl chlorides the aromatic 1,3-benzoxarsoles are obtained. The reaction proceeds via a primary attack of the arsino group. The spectroscopic data of the benzoxarsoles are discussed and compared with those of benzofurane, benzoxazole and corresponding NH-heterocycles.

o -Aminophenylarsine can be prepared in good yields by electrochemical reduction of o -nitrophenylarsonic acid. Its metallation and the reaction with alkyl halides yield the corresponding secondary o -aminophenylarsines. The As-metallated o -aminophenylarsines react with α-halocarboxylic acids to give α-( o -aminophenylarsino)carboxylic acids which cyclisize to tetrahydro-1,4-benzazarsenin-2-one. In an analogous reaction β-( o -aminophenylarsino)propionic esters can be obtained from o -aminophenylarsines and β-chloropropionic esters. The methyl ester of β-( o -aminophenylarsino)propionic acid reacts on heating to give tetrahydro-1,4-benz[ b ]methylazarsepin-2-one. All synthesized compounds have been characterized by chemical, NMR and mass spectroscopic methods.

α-Dialkylaminomethylphosphines and the corresponding arsines have been obtained by the following methods: (1) by direct Mannich reaction, (2) by reaction of secondary phosphines and arsines with bis(dimethylamino)methane, and (3) by reaction of methyleneammonium halides with secondary phosphines and arsines, silylphosphines and silylarsines, and alkali phosphides and alkali arsides, respectively. The compounds obtained show a similar reactivity as N,N-acetals. The aminomethyl group is transferred to H-acidic agents, the reaction with halides yields methylene ammonium halides and halophosphines or haloarsines, respectively. Reactivity towards methyl iodide is influenced by substituents at the phosphorus or arsenic atoms. In the case of the phosphorus compounds acetylphosphines are obtained by reaction with acetyl chloride, while the arsenic compounds add acetyl chloride to give ammonium salts.

The reaction of NaAsHR with ClCH 2 CH 2 CH 2 NH 2 yields the corresponding secondary 3-aminopropylarsines, RAs(H)CH 2 CH 2 CH 2 NH 2 , which with aldehydes and ketones form the perhydro-1,3-azarsenines. The properties and reactivity of these heterocyclic compounds are described.

The crystal and molecular structure of 5-t-butyl-5-aza-2,8-dithia-1-stanna(II)bicyclo[3.3.0 1,5 ]octane [Sn(SC 2 H 4 ) 2 NC 4 H 9 ] 2 have been determined from three-dimensional X-ray data. The crystals are monoclinic, space group P 2 1 / c , with cell dimensions: a 14.104(2), b 21.911(4), c 11.624(2) A, β 98.73(1)°, Z = 6. The final R is 0.040 for the 4279 observed reflections. The unit-cell contains four asymmetric dimers (dimer a ) and two centrosymmetric dimers (dimer b ), each dimer forms a four-membered Sn 2 S 2 ring in which the sulfur atoms are three-coordinated. The SnN distances in the two dimeric forms are significantly different (namely, 2.64 and 2.75 in dimer a , 2.97 A in dimer b ). The lengthening of the SnN distances involves the shortening of the bridging tin—sulfur bonds (2.99 and 2.79 in a , 2.71 A in b ). The coordination around the three different Sn atoms is hemispherical.

While o -substituted bromobenzene derivatives of the type o -BrC 6 H 4 XER n (X  O, S; ER n  SiMe 3 and N-BuLi undergo metal halogen exchange followed by silyl- X a C rearrangement, the corresponding compounds of phosphorus, arsenic or tin are split at the EX bond. o -Metal derivatives o -M 1 C 6 H 4 XER n (X  O, NMe; E  P, As, Sn) of these elements may be generated, however, by direct reaction with sodium or lithium. They are unstable and furnish o -hydroxy- and o -aminophenyl element(IV, V) derivatives via an intramolecular anionic rearrangement.

o -Bromoaryl esters of phosphoric acid react with magnesium to give arene phosphonic acid derivatives via intermediate Grignard compounds. Similar metallation rearrangement processes may be achieved in the case of o -chloroaryl esters if sodium is applied as metal. 2,4-Dibromoaryl esters are attacked by magnesium regiospecifically in o -position.

Zusammenfassung 1,3-Benzoxaphospholes and 1,3-benzoxarsoles undergo Diels-Alder reactions with 2,3-dimethylbutadiene and formal [4+2]-cycloadditions with tetrachloro-o-benzoquinone.

The compound 1-aza-5-stanna-5-methyltricylo[3.3.3.01,5]undecane crystallizes in the space group P21c. The unit cell, with a 7.700(1), b 9.289(3), c 16.296(5) A, V 1159.4(5) A3, β 95.89(2)°, contains four molecules. The structure was refined to a final R value of 0.042. The configuration of the tin atom is intermediate between a trigonal bipyramid and a tetrahedron. The intramolecular tin−nitrogen distance is 2.624 A.