bluuebunny/crossref_metadata_2025 huggingface dataset:
Synpolydactyly: clinical and molecular advances
Authors: Malik S , Grzeschik K‐H
Published: January 2009

Synpolydactyly (SPD) is a rare limb deformity showing a distinctive combination of syndactyly and polydactyly. Of the nine non‐syndromic syndactylies, it is clinically and genetically one of the most heterogeneous malformation. SPD families may show clinical features consistent with the Temtamy and McKusick criteria as well as additional phenotypic variants, which vary from case to case. In certain instances, these variants predominate in a given family, while the typical SPD features remain less explicit. We have reviewed all the clinical variants occurring in well‐documented SPD families. We conclude that typical SPD features can be delineated from minor clinical variants. Then, we propose to lump all the phenotypic variants, manifesting themselves in SPD families into three categories: (i) typical SPD features, (ii) minor variants, and (iii) unusual phenotypes. Next, we discuss the likely reasons for the occurrence of minor variants and the obvious lack of penetrance in SPD families. Finally, we show that for the SPD phenotype associated with HOXD13 mutations, a straightforward genotype–phenotype correlation is weak. Our lumping and splitting scheme for SPD phenotypic variants could be useful for the understanding of this interesting malformation.
Two new patients bearing mutations in the fukutin gene confirm the relevance of this gene in Walker–Warburg syndrome
Authors: Cotarelo RP , Valero MC , Prados B , Peña A , Rodríguez L , Fano O , Marco JJ , Martínez‐Frías ML , Cruces J
Published: January 2009

Walker–Warburg syndrome (WWS) is an autosomal recessive disorder characterized by congenital muscular dystrophy, brain malformations and structural abnormalities of the eye. We have studied two WWS patients born to non‐consanguineous parents, and in both cases, we identified mutations in the fukutin gene responsible for this syndrome. One of the patients carries a homozygous‐single nucleotide insertion that produces a frameshift, being this the first time that this insertion has been described in homozygosis and causing a WWS phenotype. The other patient carries two novel mutations, one being a point mutation that produces an amino acid substitution, while the other is a deletion in the 3′UTR that affects the polyadenylation signal of the fukutin gene. This deletion would probably result in the complete loss of the fukutin transcripts from this allele. This is the first time a mutation localized outside of the fukutin coding region has been identified as a cause of WWS.
Restless legs syndrome: an update on genetics and future perspectives
Authors: Pichler I , Hicks AA , Pramstaller PP
Published: January 2009

Restless legs syndrome (RLS) is a common, underdiagnosed neurological condition with an age‐dependent prevalence of up to 14%. Familial aggregation has been widely shown since Ekbom’s first description of the disorder in 1945. Five loci (12q, 14q, 9p, 2q, and 20p) have been described so far, although no positive association with any specific genes, either within these loci or additional candidates investigated, has been reported. Two recent genome‐wide association studies have reported positive association with sequence variants in or around specific genes on chromosomes 6p, 2p and 15q. The molecular findings, together with the variable expressivity of the phenotype, suggest a substantial clinical and genetic heterogeneity of RLS. This article reviews the clinical characteristics, diagnosis and epidemiology with a focus on the genetics and pathogenesis of RLS.
Familial 22q11.2 duplication: a three‐generation family with a 3‐Mb duplication and a familial 1.5‐Mb duplication
Authors: Yu S , Cox K , Friend K , Smith S , Buchheim R , Bain S , Liebelt J , Thompson E , Bratkovic D
Published: January 2009

We report two familial cases of 22q11.2 duplication detected using multiplex ligation‐dependent probe amplification (MLPA). In the first case, eight individuals from a three‐generation family were found to carry a 3‐Mb 22q11.2 duplication. The individuals carrying the duplication show phenotypic variation. This phenotypic variation includes heart defect (1 in 8 individuals, 1/8), submucous cleft palate (2/8), intellectual disability (2/8), speech delay (2/8), behaviour problems (3/8) and brachydactyly (3/8). In the second case, a 1.5‐Mb 22q11.2 duplication was detected in a neonate and her normal mother. The neonate presented with severe laryngomalacia causing intermittent stridor. Cranial ultrasound showed small subependymal cysts bilaterally. There was no heart defect or cleft palate, her chest X ray and renal ultrasound were normal. Review at 2 months of age revealed normal growth and development. Our findings broaden the understanding of 22q11.2 duplication syndrome and demonstrate that MLPA is sensitive for detection and sizing of 22q11.2 microduplications.
Novel rare mutations and promoter haplotypes in ABCA1 contribute to low‐HDL‐C levels
Authors: Slatter TL , Jones GT , Williams MJA , Van Rij AM , McCormick SPA
Published: January 2009

The ATP‐binding cassette A1 (ABCA1) protein regulates plasma high‐density lipoprotein (HDL) levels. Mutations in ABCA1 can cause HDL deficiency and increase the risk of premature coronary artery disease. Single nucleotide polymorphisms (SNPs) in ABCA1 are associated with variation in plasma HDL levels. We investigated the prevalence of mutations and common SNPs in ABCA1 in 154 low‐HDL individuals and 102 high‐HDL individuals. Mutations were identified in five of the low‐HDL subjects, three having novel variants (I659V, R2004K, and A2028V) and two with a previously identified variant (R1068H). Analysis of four SNPs in the ABCA1 gene promoter (C‐564T, G‐407C, G‐278C, and C‐14T) identified the C‐14T SNP and the TCCT haplotype to be over‐represented in low‐HDL individuals. The R1587K SNP was over‐represented in low‐HDL individuals, and the V825I and I883M SNPs over‐represented in high‐HDL individuals. We conclude that sequence variation in ABCA1 contributes significantly to variation in HDL levels.
Skewed X chromosome inactivation failed to explain the normal phenotype of a carrier female with MECP2 mutation resulting in Rett syndrome
Authors: Takahashi S , Ohinata J , Makita Y , Suzuki N , Araki A , Sasaki A , Murono K , Tanaka H , Fujieda K
Published: January 2009

Mutations in the X‐linked MECP2 gene cause Rett syndrome, a neurodevelopmental disorder that exclusively affects girls. Females with the MECP2 mutations exhibit a broad spectrum of clinical presentations ranging from classical Rett syndrome to asymptomatic carriers, which can be explained by differences in X chromosome inactivation (XCI). Here, we report a family with a girl with Rett syndrome in whom a novel missense mutation in the MECP2 gene was transmitted through the maternal germ line. The carrier mother was asymptomatic and presented non‐random XCI in the peripheral blood cells, which resulted in the X chromosome harboring the mutant allele that was predominantly active. Thus, the presence of non‐random XCI in the peripheral blood cells did not provide an explanation for the normal phenotype of the carrier mother. This result suggests that mechanisms other than XCI may contribute to the phenotypic heterogeneity associated with MECP2 mutations.
Mutations in the familial Mediterranean fever gene of patients with IgA nephropathy and other forms of glomerulonephritis
Authors: Kukuy OL , Kopolovic J , Blau A , Ben‐David A , Lotan D , Shaked M , Shinar Y , Dinour D , Langevitz P , Livneh A
Published: January 2009

Glomerulonephritis, particularly IgA nephropathy (IgAN), seems to be more common in familial Mediterranean fever (FMF), an inherited disease caused by mutations in the MEditerranean FeVer gene (MEFV). The present study is aimed to determine, in populations not suffering from FMF, whether carriage of MEFV mutations may modify or precipitate IgAN and other forms of primary glomerulonephritis (PGN). Forty patients with biopsy proven IgAN and 40 with PGN were surveyed for the presence of the three most common MEFV mutations (M694V, V726A and E148Q), using polymerase chain reaction amplification and restriction enzyme analysis. The rate of MEFV mutations in the patients was related to the expected carrier rate in the general population of the same ethnic extraction. The effect of mutation carriage on the disease course was determined in the IgAN patient group. The frequency of MEFV mutations in IgAN or PGN was comparable to that found in ethnically adjusted general population (p = 0.1 and 0.5, respectively). Carriage of mutated MEFV was not associated with the course and severity of the disease or findings in kidney biopsy and urine analysis. In a population, mostly of Jewish extraction, MEFV mutations do not seem to predispose to the development of IgAN and other forms of PGN or affect the phenotype.
Stickler and branchio‐oto‐renal syndromes in a patient with mutations in EYA1 and COL2A1 genes
Authors: Olavarrieta L , Morales‐Angulo C , Del Castillo I , Moreno F , Moreno‐Pelayo MA
Published: January 2009

Branchio‐oto‐renal (BOR) and Stickler (STL) syndromes are disorders that include hearing loss among their clinical features. STL syndrome type I (STL1) is a combination of ophthalmic, orofacial, articular, and auditory manifestations, caused by mutations in the COL2A1. BOR syndrome is an autosomal dominant trait encompassing branchial, otic and renal anomalies because of mutations in EYA1, SIX1 and SIX5. In this study, we have clinically and genetically diagnosed a proband that displayed STL1 and BOR syndromes. This patient and his younger brother exhibited hearing loss and cleft palate. Both siblings and their mother also showed myopia, congenital non‐progressive vitreous anomaly and a flat face. Taken together, these clinical features are consistent with the diagnosis of a familial case of STL. Sequence analysis revealed in the three patients a novel COL2A1 mutation (c.1468_1475delinsT) that accounted for a STL1 phenotype. The proband also displayed pre‐auricular pits, branchial fistulae and renal agenesis that define BOR syndrome. Interestingly, this patient carries an EYA1 mutation, p.R328X, which was not present in the two other patients or in his healthy father, supporting that the mutation arose de novo. In conclusion, this report highlights the importance of molecular testing and detailed clinical evaluation for the diagnosis of syndromes with overlapping phenotypic features.
Familial Mediterranean Fever in Crete: a genetic and structural biological approach in a population of ‘intermediate risk’
Authors: Fragouli E , Eliopoulos E , Petraki E , Sidiropoulos P , Aksentijevich I , Galanakis E , Kritikos H , Repa A , Fragiadakis G , Boumpas DT , Goulielmos GN
Published: January 2009

Familial Mediterranean Fever (FMF) is an autosomal, recessively inherited disease, characterized by recurrent and short attacks of fever with serosal inflammation that are caused by mutations in MEFV gene that encodes pyrin protein. To date, more than 70 disease‐associated mutations have been identified, almost all of them representing missense nucleotide changes. FMF is very common among patients with Mediterranean ancestry, although the exact prevalence is not yet known, Greeks are considered to be at ‘intermediate risk’. In the present study, we studied FMF patients in natives of Crete, a population sharing a common genetic and cultural background. The spectrum of MEFV gene mutations in 71 patients as well as 158 healthy controls was studied by performing a molecular analysis focused on the 12 most frequent FMF‐associated mutations. We found that 59 of 71 (83.1%) FMF patients had at least one MEFV mutation, five patients were homozygotes and 54 heterozygotes for FMF‐associated mutations. No mutations were detected in 12 patients (16.9%). As in high‐risk populations, common MEFV mutations were found in Cretan FMF patients, with the M694V being the most penetrant. M694V and M694I mutations were associated with severe phenotypes, with many patients presenting with uncommon clinical manifestations such as erysipelas‐like erythema or renal disturbances. Of interest, 20 (37%) of our heterozygous FMF patients presented with a severe phenotype. Population genetics analysis showed an FMF carrier frequency in healthy Cretan population of approximately 6% (1:17) and places Cretans closer to the Western rather than Eastern populations of the Mediterranean basin. Finally, we constructed a three‐dimensional model showing the interaction of the PRYSPRY domain of pyrin with caspase‐1 onto which we mapped MEFV mutations, classified according to disease severity. In this model, the ‘flexible loops’ of caspase‐1 appear to have no access to some positions that have been previously associated with mild disease, suggesting that alternative pathogenic pathways leading to FMF need to be explored.
LRP6: a link between the multiple disorders of the metabolic syndrome
Authors: Kruit JK
Published: January 2009

LRP6 mutation in a family with early coronary disease and metabolic risk factors Mani et al. (2007) Science 315: 1278–1282
RPGRIP1: a novel ciliary gene involved in cerebellar disorders
Authors: Karasinska JM
Published: January 2009

The ciliary gene RPGRIP1L is mutated in cerebello‐oculo‐renal syndrome (Joubert syndrome type B) and Meckel syndrome Delous et al. (2007) Nature Genetics 39: 875–881

Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin interactor, cause Joubert syndrome Arts et al. (2007) Nature Genetics 39: 882–888
Compound heterozygosity in the SPG4 gene causes hereditary spastic paraplegia
Authors: Pantakani DVK , Zechner U , Arygriou L , Pauli S , Sauter SM , Mannan AU
Published: January 2009

The SPG4 gene is frequently mutated in autosomal dominant form of hereditary spastic paraplegia (HSP). We report that the compound heterozygous sequence variants S44L, a known polymorphism, and c.1687G>A, a novel mutation in SPG4 cause a severe form of HSP in a patient. The family members carrying solely c.1687G>A mutation are asymptomatic for HSP. The reverse transcriptase–polymerase chain reaction (RT‐PCR) analysis revealed that the c.1687G>A mutation is a splice site mutation and causes skipping of the exon 15 of spastin. Furthermore, quantification of RT‐PCR products by sequencing and quantification of allele‐specific expression by pyrosequencing assay revealed that c.1687G>A is a leaky or hypomorphic splice site mutation. At the protein level, c.1687G>A mutation in SPG4 leads to E563K substitution. In ex vivo study, about 10% of cells expressing E563K mutant spastin showed filamentous expression pattern, suggesting a hypomorphic effect at the protein level. Collectively, our results suggest that S44L in association with c.1687G>A (E563K) drops the functional level of spastin below a threshold limit sufficient to manifest HSP.
Mucolipidosis II: a single causal mutation in the N‐acetylglucosamine‐1‐phosphotransferase gene (GNPTAB) in a French Canadian founder population
Authors: Plante M , Claveau S , Lepage P , Lavoie È‐M , Brunet S , Roquis D , Morin C , Vézina H , Laprise C
Published: January 2009

Mucolipidosis (ML) II (I‐cell disease) is a lysosomal storage disorder caused by a deficiency of UDP‐N‐acetylglucosamine:lysosomal enzyme N‐acetylglucosamine‐1‐phosphotransferase. MLII is an autosomal recessive disease with a carrier rate estimated at 1/39 in Saguenay–Lac‐Saint‐Jean (SLSJ) (Quebec, Canada), which is the highest frequency documented worldwide. To identify the causing mutation, we sequenced GNPTAB exons in 27 parents of 16 MLII‐deceased children from the SLSJ region as obligatory and potential carriers. We also performed a genealogical reconstruction for each parent to evaluate consanguinity levels and genetic contribution of ancestors. Our goal was to identify which parameters could explain the high MLII frequency observed in the SLSJ population. A single mutation (c.3503_3504delTC) was found in all obligatory carriers. In addition, 11 apparent polymorphisms were identified. The mutation was not detected in genomic DNA of 50 unrelated controls. Genealogical data show six founders (three couples) with a higher probability of having introduced the mutation in the population. The frequency of the mutation was increased as a consequence of this founder effect and of the resulting population structure. We suggest that c.3503_3504delTC is the allele causing MLII in the SLSJ population, and its high carrier rate is most likely explained by a founder effect.
A novel locus for dHMN with pyramidal features maps to chromosome 4q34.3‐q35.2
Authors: Muglia M , Magariello A , Citrigno L , Passamonti L , Sprovieri T , Conforti FL , Mazzei R , Patitucci A , Gabriele AL , Ungaro C , Bellesi M , Quattrone A
Published: January 2009

The distal hereditary motor neuropathy (dHMN) is a rare genetically and clinically heterogeneous disorder characterized by weakness and wasting of distal limb muscles in absence of overt sensory abnormalities. Recently, pyramidal signs have been also described in some patients with dominant or recessive dHMN, and two different loci have been identified in families affected by dHMN complicated with pyramidal dysfunction. We investigated an Italian family affected by an autosomal dominant dHMN complicated by pyramidal signs in order to map a new gene locus. The disease maps to a novel locus in a 26‐cM region flanked by D4S1552 and D4S2930 on chromosome 4q34.3‐35.2. Three candidate genes (SNX25, CASP3 and TUBB4Q) located in the critical region were screened for the presence of mutations by heteroduplex analysis. No mutations have been detected in the analyzed genes. In conclusion, the new private genetic locus we reported further confirms the wide heterogeneity of dHMN.
Advances in the genetics of sarcoidosis
Authors: Smith G , Brownell I , Sanchez M , Prystowsky S
Published: January 2009

Sarcoidosis is an uncommon disease of granulomatous inflammation. Genetic predisposition to sarcoidosis is indicated by observations of familial clustering, increased concordance in monozygotic twins over other siblings, and variations in susceptibility and disease presentation among different ethnic groups. Published studies on sarcoidosis have investigated a variety of genetic associations. These studies used techniques ranging from classic human lymphocyte antigen genotype correlations to genome‐wide linkage scans. Results have both supported and refuted disease associations with a number of genes potentially involved in the pathogenesis of sarcoidosis. Here, we review representative studies concerning the genetics of sarcoidosis. While investigations to date have failed to identify a unifying genetic signature associated with sarcoidosis, numerous studies have identified genetic associations with disease subtypes or within specific populations. These studies suggest that genetic susceptibility to sarcoidosis is complex and polygenic in nature. Future studies will help clarify the genetics of sarcoidosis and allow for the development of diagnostic, prognostic and therapeutic technologies.
Analysis of β globin mutations in the Indian population: presence of rare and novel mutations and region‐wise heterogeneity
Authors: Edison ES , Shaji RV , Devi SG , Moses A , Viswabandhya A , Mathews V , George B , Srivastava A , Chandy M
Published: January 2009

β Thalassaemia is a major public health problem in India. A comprehensive database of the spectrum of mutations causing β thalassaemia in the Indian population is necessary. This study in which a large number of patients with β thalassaemia including those from certain regions that were not explored earlier shows a great heterogeneity of mutations. Several novel and rare alleles that have not been reported earlier in the Indian population have been identified, and mutations differ in frequency in different regions of the country. This information on the spectrum of mutations has implications for the control of β thalassaemia in a population with complex ethnic background and also on the genotype–phenotype correlation of the disease.
Three novel mutations in the PORCN gene underlying focal dermal hypoplasia
Authors: Leoyklang P , Suphapeetiporn K , Wananukul S , Shotelersuk V
Published: January 2009

Focal dermal hypoplasia (FDH) is an X‐linked dominant disorder characterized by patchy dermal hypoplasia with digital, ocular and dental abnormalities. Very recently, mutations in the PORCN gene were demonstrated to cause FDH. Here, we described three unrelated Thai girls who were sporadic cases of FDH. One of them had unilateral athelia, which has never been described in FDH. Mutation analysis by polymerase chain reaction sequencing the entire coding regions of PORCN successfully revealed three potentially pathogenic mutations, c.373+1G>A, c.737_738insA and c.1094G>A (p.R365Q). One was found in each of three patients. In addition, another sequence variant c.682C>T (p.R228C) with an inconclusive role was found in one patient and her unaffected mother. The two missense mutations were not detected in at least 100 ethnic‐matched control chromosomes, and all four mutations had never been previously described. X chromosome inactivation studies showed random patterns in all of them. This study demonstrates that PORCN is the gene responsible for FDH across different populations and extends the total number of confirmed mutations to 26.
Loss of dynamic histone regulation underlies mental retardation
Authors: Grant ME
Published: January 2009

The X‐linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases Iwase et al. (2007) Cell 128: 1077–1088

The histone H3K4 demethylase SMCX links REST target genes to X‐linked mental retardation Tahiliani et al. (2007) Nature 447: 601–606
Huntington disease‐like 2: the first patient with apparent European ancestry
Authors: Santos C , Wanderley H , Vedolin L , Pena SDJ , Jardim L , Sequeiros J
Published: January 2009

Huntington disease‐like 2 (HDL2) is a rare autosomal dominant disorder of the nervous system, apparently indistinguishable from Huntington disease (HD). HDL2 is caused by the expansion above 40 CTG/CAG repeats, in a variably spliced exon of the junctophilin‐3 gene, on chromosome 16q24.3. All patients described so far have been of African ancestry. A clinical evaluation, including the Unified Huntington’s Disease Rating Scale, and brain Magnetic resonance imaging were achieved in a 48‐year‐old Brazilian man of apparent European extraction, and presenting a picture very suggestive of HD. Gene mutation analysis (HD, HDL1, HDL2, dentatorubralpallidoluysian atrophy and spinocerebellar ataxia 17) was performed. After exclusion of the HD mutation and other HDL disorders, we identified an expansion of 47 CTG/CAG at the HDL2 locus. To clarify the origin of the mutation and estimate the patient’s ancestry, we performed haplotype studies and used the insertion/deletion polymorphisms method. Despite the fact that this patient had an estimated likelihood of 97.4% of being of European ancestry, the haplotype containing the expanded allele has been found only in Africans. Thus, this is the first HDL2 case reported in a patient with an apparent European ancestry, although bearing an African HDL2 haplotype. This work stresses the importance of performing the diagnosis of HDL2 in HD‐like patients of various ethnicities, and particularly in highly mixed populations.
Mutations of carnitine palmitoyltransferase II (CPT II) in Japanese patients with CPT II deficiency
Authors: Yasuno T , Kaneoka H , Tokuyasu T , Aoki J , Yoshida S , Takayanagi M , Ohtake A , Kanazawa M , Ogawa A , Tojo K , Saito T
Published: January 2009

Carnitine palmitoyltransferase II (CPT II) deficiency is an inherited disorder involving β‐oxidation of long‐chain fatty acids. CPT II deficiency is a wide‐spectrum disorder that includes a lethal neonatal form, an infantile form, and an adult‐onset form. However, the ethnic characteristics and the relationship between genotype and clinical manifestation are not well understood. We investigated three non‐consanguineous Japanese patients with CPT II deficiency and examined cell lines from 4 unrelated patients and 50 healthy donors. The CPT 2 gene was typed by direct DNA sequencing of polymerase chain reaction‐amplified gene products. Case 1 (infantile form) was heterozygous for a phenylalanine to tyrosine substitution at position 383 (p.F383Y) and a novel valine to leucine substitution at 605 (p.V605L). Cases 2, 4, and 5 (infantile form) and case 3 (adult‐onset form) were heterozygous for a single mutation at F383Y. Case 6 (adult‐onset form) was compound heterozygous at the CPT 2 locus, with deletion of cytosine and thymine at residue 408, resulting in a stop signal at 420 (p.Y408fsX420), and an arginine to cysteine substitution at position 631 (p.R631C). Case 7 (adult‐onset form) was homozygous for the p.F383Y mutation. In conclusion, we identified p.F383Y mutations in six of seven patients with CPT II deficiency and two novel variants of the coding gene: p.Y408fsX420 and p.V605L. These mutations differ from those in Caucasian patients, who commonly harbor p.S113L, p.P50H, and p.Q413fsX449 mutations; therefore, our data and those of other Japanese groups suggest that the p.F383Y mutation is significant in Japanese patients with CPT II deficiency.
Genotyping microarray as a novel approach for the detection of ATP7B gene mutations in patients with Wilson disease
Authors: Gojová L , Jansová E , Külm M , Pouchlá S , Kozák L
Published: January 2009

Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism that is caused by mutations in the ATP7B gene. To date, more than 300 mutations have been described in this gene. Molecular diagnostics of WD utilizes restriction enzyme digestion, multiplex ligation‐dependent probe amplification or a direct sequencing of the whole gene. To simplify and speed up the screening of ATP7B mutations, we have developed a genotyping microarray for the simultaneous detection of 87 mutations and 17 polymorphisms in the ATP7B gene based on the arrayed primer extension reaction. The patient’s DNA is amplified in four multiplex polymerase chain reactions, fragmented products are annealed to arrayed primers spotted on a chip, which enables DNA polymerase extension reactions with fluorescently labeled dideoxynucleotides. The Wilson microarray was validated by screening 97 previously genetically confirmed WD patients. In total, we detected 43 mutations and 15 polymorphisms that represent a majority of the common mutations occurring in the Czech and Slovak populations. All screened sequence variants were detected with 100% accuracy. The Wilson chip appears to be a rapid, sensitive and cost‐effective tool, representing the prototype of a disease chip that facilitates and speeds up the screening of potential WD patients.
Genetic causes of chronic pancreatitis: the elucidation of genetic contributions to a disorder once thought to have none
Authors: Kang MH
Published: January 2009

Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis Jonas Rosendahl et al. (2008) Nature Genetics 40: 78–82
Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings
Authors: Miyoshi Y , Akagi M , Agarwal AK , Namba N , Kato‐Nishimura K , Mohri I , Yamagata M , Nakajima S , Mushiake S , Shima M , Auchus RJ , Taniike M , Garg A , Ozono K
Published: January 2009

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome, characterized by mandibular hypoplasia, acroosteolysis affecting distal phalanges and clavicles, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. Recently, mutations in lamin A/C (LMNA) and zinc metalloprotease (ZMPSTE24), involved in post‐translational processing of prelamin A to mature lamin A, have been identified in MAD kindreds. We now report novel compound heterozygous mutations in exon 1 (c.121C>T; p.Q41X) and exon 6 (c.743C>T; p.P248L) in ZMPSTE24 in two Japanese sisters, 7‐ and 3‐year old, with severe MAD and characteristic facies and atrophic skin. The older sister had lipodystrophy affecting the chest and thighs but sparing abdomen. Their parents and a brother, who were healthy, had heterozygous mutations. The missense mutation, P248L, was not found in 100 normal subjects of Japanese origin. The mutant Q41X was inactive in a yeast halo assay; however, the mutant P248L retained near normal ZMPSTE24 activity. Immunoblots demonstrated accumulation of prelamin A in the patients’ cell lysates from lymphoblasts. The lymphoblasts from the patients also revealed less intense staining for lamin A/C on immunofluorescence. We conclude that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.
Genomic and functional analyses of MUTYH in Japanese patients with adenomatous polyposis
Authors: Yanaru‐Fujisawa R , Matsumoto T , Ushijima Y , Esaki M , Hirahashi M , Gushima M , Yao T , Nakabeppu Y , Iida M
Published: January 2009

The present study was undertaken to elucidate germ line mutations of the base excision repair gene, MUTYH, in Japanese patients with adenomatous polyposis. We screened germ line mutations of adenomatous polyposis coli (APC) gene and MUTYH in 66 Japanese patients with adenomatous polyposis. APC was screened by the protein truncation test, while MUTYH was screened by polymerase chain reaction‐based single‐strand conformation polymorphism and direct sequencing. The nicking assay was applied in order to evaluate the DNA glycosylase activity of the identified MUTYH variant. In this study, Seven MUTYH variants were identified in 16 of 21 APC‐negative patients. Q324H mutation was the most frequent mutation, with an allele frequency of 49%. Two patients carried biallelic mutations other than Q324H; a patient had biallelic G272E and A359V mutations, while the other had compound heterozygotes of P18L and G25D mutations. Nicking assay for G272E using the corresponding mouse MUTYH mutant with G257E revealed that G272E is a variant to cause an impaired DNA glycosylase activity. Homozygous MUTYH mutation accounts for approximately 10% of Japanese patients with adenomatous polyposis. G272E may be one of the mutations specific to patients with adenomatous polyposis in East Asia.
Silent exonic mutations in the low‐density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing
Authors: Defesche JC , Schuurman EJM , Klaaijsen LN , Khoo KL , Wiegman A , Stalenhoef AFH
Published: January 2009

In a large group of patients with the clinical phenotype of familial hypercholesterolemia, such as elevated low‐density lipoprotein (LDL) cholesterol and premature atherosclerosis, but without functional mutations in the genes coding for the LDL receptor and apolipoprotein B, we examined the effect of 128 seemingly neutral exonic and intronic DNA variants, discovered by routine sequencing of these genes. Two variants, G186G and R385R, were found to be associated with altered splicing. The nucleotide change leading to G186G resulted in the generation of new 3′‐splice donor site in exon 4 and R385R was associated with a new 5′‐splice acceptor site in exon 9 of the LDL receptor gene. Splicing of these alternate splice sites leads to an in‐frame 75‐base pair deletion in a stable mRNA of exon 4 in case of G186G and R385R resulted in a 31‐base pair frame‐shift deletion in exon 9 and non‐sense‐mediated mRNA decay.
Dyschromatosis universalis hereditaria: evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21‐q23
Authors: Stuhrmann M , Hennies HC , Bukhari IA , Brakensiek K , Nürnberg G , Becker C , Huebener J , Miranda MC , Frye‐Boukhriss H , Knothe S , Schmidtke J , El‐Harith E‐HA
Published: January 2009

Dyschromatosis universalis hereditaria (DUH) and dyschromatosis symmetrica hereditaria (DSH) are pigmentary dermatoses most commonly seen in Japan. Both disorders usually show autosomal dominant inheritance, although in some cases autosomal recessive inheritance was reported. DSH was mapped to chromosome 1q21.3, and mutations in the gene ADAR (DSRAD) were identified in Japanese, Chinese and Taiwanese families with autosomal dominant DSH. A second locus for dyschromatosis was mapped on chromosome 6q24.2‐q25.2 in two Chinese families initially reported to be affected with DSH, but later suggested to have autosomal dominant DUH. The aim of this study was to investigate whether one of these two loci is involved in the development of DUH in a consanguineous Bedouin family from Saudi Arabia with four affected and three unaffected sibs, clearly pointing to autosomal recessive inheritance. After excluding mutations in ADAR and linkage to the candidate regions on chromosomes 1 and 6, we performed an single nucleotide polymorphism‐based genome‐wide scan for linkage with other loci. Under the assumption of autosomal recessive inheritance, we have identified a new locus for dyschromatosis on chromosome 12q21‐q23 in this Arab family with a maximum logarithm of the odds (LOD) score of 3.4, spanning a distance of 18.9 cM. Our study revealed the first locus for autosomal recessive DUH and supports recent evidence that DSH and DUH are genetically distinct disorders.
Homozygous FGF3 mutations result in congenital deafness with inner ear agenesis, microtia, and microdontia
Authors: Tekin M , Öztürkmen Akay H , Fitoz S , Birnbaum S , Cengiz FB , Sennaroğlu L , İncesulu A , Yüksel Konuk EB , Hasanefendioğlu Bayrak A , Şentürk S , Cebeci İ , Ütine GE , Tunçbilek E , Nance WE , Duman D
Published: January 2009

Homozygous mutations in the fibroblast growth factor 3 (FGF3) gene have recently been discovered in an autosomal recessive form of syndromic deafness characterized by complete labyrinthine aplasia (Michel aplasia), microtia, and microdontia (OMIM 610706 – LAMM). In order to better characterize the phenotypic spectrum associated with FGF3 mutations, we sequenced the FGF3 gene in 10 unrelated families in which probands had congenital deafness associated with various inner ear anomalies, including Michel aplasia, with or without tooth or external ear anomalies. FGF3 sequence changes were not found in eight unrelated probands with isolated inner ear anomalies or with a cochlear malformation along with auricle and tooth anomalies. We identified two new homozygous FGF3 mutations, p.Leu6Pro (c.17T>C) and p. Ile85MetfsX15 (c.254delT), in four subjects from two unrelated families with LAMM. The p.Leu6Pro mutation occurred within the signal site of FGF3 and is predicted to impair its secretion. The c.254delT mutation results in truncation of FGF3. Both mutations completely co‐segregated with the phenotype, and heterozygotes did not have any of the phenotypic findings of LAMM. Some affected children had large skin tags on the upper side of the auricles, which is a distinctive clinical component of the syndrome. Enlarged collateral emissary veins associated with stenosis of the jugular foramen were noted on computerized tomographies of most affected subjects with FGF3 mutations. However, similar venous anomalies were also detected in persons with non‐syndromic Michel aplasia, suggesting that a direct causative role of impaired FGF3 signaling is unlikely.
Autosomal recessive ichthyosis with hypotrichosis syndrome: further delineation of the phenotype
Authors: Avrahami L , Maas S , Pasmanik‐Chor M , Rainshtein L , Magal N , Smitt JHS , Van Marle J , Shohat M , Basel‐Vanagaite L
Published: January 2009

Autosomal recessive ichthyosis with hypotrichosis (ARIH) syndrome, which is characterized by congenital ichthyosis, abnormal hair and corneal involvement, has recently been shown in one consanguineous Israeli Arab family to be caused by a mutation in the ST14 gene, which encodes serine protease matriptase. No other families have so far been described since the original report. In this current report we describe a female patient from a second family with ARIH syndrome who carries a homozygous novel mutation, p.M1I. The patient has congenital ichthyosis, light brown, curly, sparse hair, improving with age, and sparse body hair, eyebrows and eyelashes. She does not suffer from photophobia, but has blepharitis. The phenotype of this patient closely resembles that of the affected individuals in the previously reported family, although she does not have tooth abnormalities and the ichthyosis is milder.
Concurrent microdeletion and duplication of 22q11.2
Authors: Blennow E , Lagerstedt K , Malmgren H , Sahlén S , Schoumans J , Anderlid BM
Published: January 2009

Microduplication of 22q11.2 has been reported in fewer than 40 cases, all of them including the DiGeorge critical region (DGCR). We here present the characterization of a new duplication that does not include the DGCR. The duplication was initially found by multiplex ligation‐dependent probe amplification analysis of 22q11.2 in a young girl with a concurrent deletion of the DGCR in 70% of her peripheral blood lymphocytes. Her phenotype included many of the features of the velocardiofacial syndrome, with velopharyngeal insufficiency, recurrent infections, learning and concentration problems as well as difficulties in social interactions. However, there were no congenital malformations, and her facial appearance was not typical for the syndrome. Further investigations included array comparative genomic hybridization (CGH) to size map the deletion/duplication and interphase fluorescent in situ hybridization to investigate mosaicism and the structure of the rearrangement. An identical duplication of this part of 22q11.2 has not been reported before, and the duplication itself seems to be associated with very mild or no symptoms. This study contributes to the growing knowledge regarding new deletions and duplications of 22q11.2, most of them mediated by the pre‐disposing high number of low‐copy repeats in the region.
A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2)
Authors: Jelani M , Wasif N , Ali G , Chishti MS , Ahmad W
Published: January 2009

Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on scalp and rest of the body of affected subjects. Recently, three clinically similar autosomal recessive forms of hypotrichosis [localized autosomal recessive hypotrichosis (LAH)1], LAH2 and LAH3 have been mapped on chromosomes 18q12.1, 3q27.3, and 13q14.11‐q21.32, respectively. For these three loci, two genes DSG4 for LAH1 and LIPH for LAH2 have been identified. To date, only five mutations in DSG4 and two in LIPH genes have been reported. In this study, we have ascertained two large unrelated consanguineous Pakistani families with autosomal recessive form of hypotrichosis. Affected individuals showed homozygosity to the microsatellite markers tightly linked to LIPH gene on chromosome 3q27. Sequence analysis of the gene in the affected subjects from both the families revealed a novel deletion mutation in exon 5 (c.659‐660delTA) causing frameshift and downstream premature termination codon. All the three mutations identified in the LIPH gene, including the one in this study, are deletion mutations.
Early age‐of‐onset iron overload and homozygosity for the novel hemojuvelin mutation HJV R54X (exon 3; c.160A→T) in an African American male of West Indies descent
Authors: Murugan RC , Lee PL , Kalavar MR , Barton JC
Published: January 2009

An African American male of West Indies descent was diagnosed to have elevated transferrin saturation, hyperferritinemia, severe iron deposition in hepatocytes, and hepatic cirrhosis at age 4. He was treated with serial phlebotomy to maintain a normal serum ferritin concentration thereafter. We evaluated him at age 23 and confirmed that he had normal serum ferritin levels, severe iron deposition in hepatocytes, hepatic cirrhosis, and portal hypertension. He did not have endocrinopathy, cardiomyopathy, or arthropathy. He was homozygous for the novel hemojuvelin (HJV) premature stop‐codon mutation R54X (exon 3; c.160A→T). He did not have either HFE C282Y, H63D, or S65C, or deleterious coding region mutations of SLC40A1, TFR2, or HAMP. His erythrocyte measures and hemoglobin electrophoresis were consistent with alpha‐thalassemia trait. We conclude that homozygosity for HJV R54X accounts for his severe, early age‐of‐onset hemochromatosis; his phenotype was probably modified by serial phlebotomy therapy.
Age and origin of the G774A mutation inSLC22A12causing renal hypouricemia in Japanese
Authors: Ichida K , Hosoyamada M , Kamatani N , Kamitsuji S , Hisatome I , Shibasaki T , Hosoya T
Published: January 2009

Renal hypouricemia is an inherited disorder characterized by impaired tubular uric acid transport. Impairment of the function of URAT1, the main transporter for the reabsorption of uric acid at the apical membrane of the renal tubules, causes renal hypouricemia. The G774A mutation in theSLC22A12gene encoding URAT1 predominates in Japanese renal hypouricemia. From data on linkage disequilibrium between the G774 locus and the 13 markers flanking it (12 single nucleotide polymorphisms and 1 dinucleotide insertion/deletion locus), we here estimate the age of this mutation at approximately 6820 years [95% confidence interval (CI) 1860–11,760 years; median = 2460 years]. This indicates that the origin of the G774A mutation dates back from between the time when the Jomon people predominated in Japan and the time when the Yayoi people started to migrate to Japan from the Korean peninsula. These data are consistent with a recent finding that this G774A mutation was also predominant in Koreans with hypouricemia and indicate that the mutation originated on the Asian continent. Thus, this mutation found in Japanese patients was originally brought by immigrant(s) from the continent and thereafter expanded in the Japanese population either by founder effects or by genetic drift (or both).
Dysmorphic syndrome of hereditary neuralgic amyotrophy associated with a SEPT9 gene mutation – a family study
Authors: Laccone F , Hannibal MC , Neesen J , Grisold W , Chance PF , Rehder H
Published: January 2009

We report a family in which two siblings presented with an apparent dysmorphic syndrome, including hypotelorism, blepharophimosis, slight ptosis, epicanthal folds, microstomia and dysmorphic ears. One sibling had a cleft palate. Initially, blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) was suspected; however, mutation of the FOXL2 gene was not detected. Moreover, the patients’ father and paternal grandmother had experienced recurrent episodes of unilateral brachial neuritis and were diagnosed to have hereditary neuralgic amyotrophy (HNA). HNA is a rare, inherited form of brachial neuritis whose phenotypic spectrum may include hypotelorism, cleft palate and other minor dysmorphisms. HNA maps to chromosome 17q25 and is associated with mutations in the SEPT9 gene. After confirming a heterozygous SEPT9 mutation (R88W) in the father and his mother, it became apparent that the dysmorphic features in the children were part of HNA and that previous complaints of the daughter, erroneously diagnosed as pronatio dolorosa and then epiphysiolysis of the capitellum humeri, were in fact a first neuralgic pain attack. Both children were shown to have inherited the paternal SEPT9 mutation. Wider recognition of HNA as a syndromic disorder may facilitate its diagnosis in affected young persons who may not yet have manifested episodes of brachial neuritis.
Genetic heterogeneity and minor CYP1B1 involvement in the molecular basis of primary congenital glaucoma in Gypsies
Authors: Sivadorai P , Cherninkova S , Bouwer S , Kamenarova K , Angelicheva D , Seeman P , Hollingsworth K , Mihaylova V , Oscar A , Dimitrova G , Kaneva R , Tournev I , Kalaydjieva L
Published: January 2009

Primary congenital glaucoma (PCG) is a genetically heterogeneous disorder of autosomal recessive inheritance, with mutations in the cytochrome P450 1B1 (CYP1B1) gene detected in an average of ∼50% of cases worldwide. The Roma/Gypsies are considered to be a rare example of a single founder CYP1B1 mutation, E387K (identified in the Slovak Roma), accounting for 100% of disease alleles. Contrary to this concept, unusual genetic heterogeneity was revealed in this study of 21 Gypsy PCG patients from Bulgaria and 715 controls from the general Gypsy population. In our small sample of affected subjects, we identified five different CYP1B1 mutations – four known (E229K, R368H, E387K and R390C) and one novel and potentially pathogenic (F445I), which together accounted for ∼30% of disease alleles. E387K was rare in both the patient and the control group, indicating that its high frequency in the Slovak Roma is the product of local founder effect not representative of the overall molecular pattern of PCG in the Gypsy population. Data on other Mendelian disorders and on the population genetics of the Gypsies suggest that a true founder mutation is likely to exist and has remained undetected. Our analysis of another candidate gene, MYOC, and the GLC3B and GLC3C loci did not provide support for their involvement. The molecular basis of PCG in the Gypsies is thus unresolved, and diagnostic analyses should be extended beyond the E387K mutation.
Autism‐associated familial microdeletion of Xp11.22
Authors: Qiao Y , Liu X , Harvard C , Hildebrand MJ , Rajcan‐Separovic E , Holden JJA , Lewis MES
Published: January 2009

We describe two brothers with autistic disorder, intellectual disability (ID) and cleft lip/palate with a microdeletion of Xp11.22 detected through screening individuals with autism spectrum disorders (ASDs) for microdeletions and duplications using 1‐Mb resolution array comparative genomic hybridization. The deletion was confirmed by fluorescence in situ hybridization/real‐time quantitative polymerase chain reaction (RT‐qPCR) and shown to be inherited from their unaffected mother who had skewed (100%) X inactivation of the aberrant chromosome. RT‐qPCR characterization of the del(X)(p11.22) region (∼53,887,000–54,359,000 bp) revealed complete deletion of the plant homeodomain finger protein 8 (PHF8) gene as well as deletions of the FAM120C and WNK lysine‐deficient protein kinase 3 (WNK3) genes, for which a definitive phenotype has not been previously characterized. Xp11.2 is a gene‐rich region within the critical linkage interval for several neurodevelopmental disorders. Rare interstitial microdeletions of Xp11.22 have been recognized with ID, craniofacial dysmorphism and/or cleft lip/palate and truncating mutations of the PHF8 gene within this region. Despite evidence implicating genes within Xp11.22 with language and cognitive development that could contribute to an ASD phenotype, their involvement with autism has not been systematically evaluated. Population screening of 481 (319 males/81 females) and 282 X chromosomes (90 males/96 females) in respective ASD and control cohorts did not identify additional subjects carrying this deletion. Our findings show that in addition to point mutations, a complete deletion of the PHF8 gene is associated with the X‐linked mental retardation Siderius‐Hamel syndrome (OMIM 300263) and further suggest that the larger size of the Xp11.22 deletion including genes FAM120C and WNK3 may be involved in the pathogenesis of autism.