Array-comparative Genomic Hybridization Results in Clinically Affected Cases with Apparently Balanced Chromosomal Rearrangements.

Carriers of apparently balanced chromosomal rearrangements (ABCRs) have a 2-3-fold higher risk of carrying an abnormal phenotype, when compared to the average population. Apparently balanced chromosomal rearrangements can be imbalanced at the submicroscopic level, and changes in the gene structure, formation of a new chimeric gene, gain or loss of function of the genes and altered imprinting pattern may also affect the phenotype. Chromosomal microarray (CMA) is an efficient tool to detect submicroscopic imbalances at the breakpoints as well as in the whole genome. We aimed to determine the effectiveness of array-comparative genomic hybridization (aCGH) application in phenotypically affected cases with ABCRs at a single center from Turkey. Thirty-four affected cases (13 prenatal, 21 postnatal) carrying ABCRs were investigated with CMA. In postnatal series, ABCRs were familial in 7 and de novo in 14 cases. Seven de novo cases were imbalanced (in postnatal series 33.3% and in de novo cases 50.0%). Out of 13 prenatal cases, five were familial and eight were de novo in origin and two de novo cases were imbalanced (in 15.4% prenatal series and in 25.0% de novo cases). No cryptic imbalance was observed in familial cases. The anomaly rates with array studies ranged between 14.3-25.0% in familial and between 20.0-57.5% in de novo cases of postnatal series in the literature. Studies focused on prenatal ABCR cases with abnormal ultrasound findings are limited and no submicroscopic imbalance was reported in the cohorts. When de novo postnatal or prenatal results were combined, the percentage of abnormalities detected by CMA was 40.9%. Taking this contribution into consideration, all ABCRs should be investigated by CMA even if the fetal ultrasound findings are normal.

Mutation spectrum of 260 dystrophinopathy patients from Turkey and important highlights for genetic counseling.

We genetically evaluated 260 dystrophinopathy patients from Turkey. Karyotyping as an initial test in female patients, followed stepwise by multiplex ligation-dependent probe amplification and by targeted next-generation sequencing of DMD revealed definitive genetic diagnoses in 214 patients (82%), with gross deletions/duplications in 153 (59%), pathogenic sequence variants in 60 (23%), and X-autosome translocation in one. Seven of the gross and 27 of the sequence variants found novel. In silico prediction, co-segregation and transcript assays supported the pathogenic nature of the novel silent (p.Lys534=) and the splice site (c.4345-12C>G) alterations. From a total of 189 singleton cases, 154 (82%) had pathogenic alterations. From 138 of those who had maternal carrier testing, 68 out of 103 (66%) showed gross and 11 out of 35 (31%) showed small pathogenic variants. This suggests that the de novo occurrences in DMD appear approximately 2.1 times more frequently in meiotic unequal crossing-over than in uncorrected replication errors. Our study also disclosed three mothers as obligate gonadal mosaic carriers. Family-based investigation of dystrophinopathy patients is crucial for the ascertainment of novel or rare variants and also for counseling and follow-up care of the families.

Diagnostic impact of 18F-FDG PET/CT on the management of rare breast carcinomas: Apocrine and neuroendocrine carcinomas. / Impacto diagnóstico de la PET/TC con 18F-FDG en el tratamiento de carcinomas de mama raros: carcinomas apocrinos y neuroendocrinos.

OBJECTIVE: We aimed to evaluate the diagnostic impact of 18F-FDG PET/CT in staging apocrine breast carcinoma (ABC) and primary breast neuroendocrine carcinoma (PBNEC) and to demonstrate possible alterations of the 18F-FDG uptake in these histopathologic subtypes. In addition, we aimed to compare 18F-FDG PET/CT findings between ABC, PBNEC and invasive ductal carcinoma. MATERIAL AND METHODS: A total of 570 patients and 585 breast lesions were retrospectively included in this study. After patients were classified into molecular subtypes according to the histopathological analysis, 18F-FDG PET/CT imaging was performed. The SUVmax findings of primary tumors obtained from 18F-FDG PET/CT were compared between the groups. RESULTS: Invasive ductal carcinoma was the most prevalent breast carcinoma (77.7%, n=446), with a low proportion of ABC (4.1%, n=24) and PBNEC (2.4%; n=14) diagnosed. The highest mean SUVmax was calculated in HER2 subtype of ABC and 18F-FDG uptake ratio in HER2 and TN subtypes were found statistically higher than Luminal B type of ABC (p=0.038 and p=0.019, respectively). Although 18F-FDG uptake in Luminal B subtype of PBNEC was higher than Luminal A subtype, difference was not statistically significant. Additionally, the axillary metastasis rate was significantly higher in the ABC group (p=0.015). CONCLUSIONS: The histopathological ABC subtype group showed different 18F-FDG uptake than the invasive ductal carcinoma group. Even if 18F-FDG uptake was lower in the PBNEC group than in the other groups, PET/CT showed and adequate performance in detecting primary tumors and metastases. The 18F-FDG PET/CT scan results may contribute to the initial staging and management of ABC and PBNEC patients.

TWIST1 Gene Expression as a Biomarker for Predicting Primary Doxorubicin Resistance in Breast Cancer.

Doxorubicin is one of the most commonly used chemotherapeutic agents for adjuvant chemotherapy of breast cancer. In the studies focused on finding biomarkers to predict the response of the patients and tumors to the drugs used, the Twist transcription factor has been suggested as a candidate biomarker for predicting chemo-resistance of breast tumors. In this study, we aimed to investigate the relationship between TWIST transcription factor expression and the effectiveness of doxorubicin treatment on directly taken primary tumor samples from chemotherapy-naive breast cancer patients. Twenty-six primary breast tumor samples taken from 26 different breast cancer patients were included in this study. Adenosine triphosphate tumor chemo-sensitivity assay (ATP-TCA) has been used to determine tumor response to doxorubicin and real-time reverse-transcription polymerase chain reaction (RT-PCR) was used for analyzing the TWIST1 gene expression of tumors. There was a significant difference in TWIST gene expression between responder and non responder tumors (p <0.05). The TWIST gene expression of the drug-resistant group was higher than the responsive group. This difference was not dependent on the histopathological features of tumors. In conclusion, compatible with earlier studies that have been performed with cell lines, the current study supports the role of higher TWIST gene expression as a biomarker for predicting the response of breast tumors to chemo-therapeutic agent doxorubicin.

Turkish Adaptation of Dentine Hypersensitivity Experience Questionnaire (DHEQ).

OBJECTIVE: The Dentine Hypersensitivity Experience Questionnaire (DHEQ) is a valid and reliable instrument for oral health-related quality of life (OHRQoL) studies. This study aimed to assess the Turkish version of the DHEQ and determine the effects of degree of DH, sex, and age on OHRQoL. MATERIALS: The study participants were 251 DH patients (age 18-78 years; 68.5% female) who completed the Turkish version of the DHEQ. The reliability of the instrument was assessed in terms of internal consistency, using item-total correlations and Cronbach's alpha and test-retest reliability using intra-class correlation coefficients (ICCs) among 51 patients who repeated the DHEQ following a 2-week interval. Construct validity was determined based on exploratory factor analysis (EFA). Convergent validity was tested through correlating DHEQ total and subscale scores with the global rating of oral health and effect on life overall. Discriminative validity was tested by comparing the total and subscale scores against the degree of sensitivity. RESULTS: Patients with more severe hypersensitivity showed higher DHEQ scores and greater OHRQoL impairment. Female and older (⟩40 years) patients had significantly greater OHRQoL impairment. Cronbach's alpha exceeded 0.70, indicating good internal consistency reliability. The ICC values measured were ⟩0.60 for the overall scale and each subscale of the DHEQ, signifying good to excellent test-retest reliability. CONCLUSION: The results suggested that the Turkish version of the DHEQ is appropriate for assessing the OHRQoL among people with dentine hypersensitivity.

Rapid emergence of colistin resistance and its impact on fatality among healthcare-associated infections.

This article describes the emergence of resistance and predictors of fatality for 1556 cases of healthcare-associated Gram-negative bloodstream infection in 2014 and 2015. The colistin resistance rate in Klebsiella pneumoniae was 16.1%, compared with 6% in 2013. In total, 660 (42.4%) cases were fatal. The highest fatality rate was among patients with Acinetobacter baumannii bacteraemia (58%), followed by Pseudomonas aeruginosa (45%), Klebsiella pneumoniae (41%), Enterobacter cloacae (32%) and Escherichia coli (28%). On multi-variate analysis, the minimum inhibitory concentrations for carbapenems [odds ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.04; P = 0.002] and colistin (OR 1.1, 95% CI 1.03-1.17; P = 0.001) were found to be significantly associated with fatality.

Risk factors for mortality in geriatric hip fractures: a compressional study of different surgical procedures in 785 consecutive patients.

BACKGROUND: Only a little is known about whether type of surgical intervention has an effect on mortality of these patients. Our primary objective was to assess whether different type of surgical procedures has an effect on mortality among elderly patients with hip fracture. A secondary objective was to examine factors that are related to mortality in our patient population. Our hypothesis is that type of surgical procedure, especially external fixation, should have an influence on mortality outcomes. METHODS: We included 785 patients age 65 years or older, with hip fractures. Operative treatment consisted of external fixation, internal fixation, total hip arthroplasty and hip hemiarthroplasty. Age, gender, type of fracture, type of surgery performed, American Society of Anesthesiology (ASA) grade, clinical comorbidities, anesthesia type, blood transfusion requirement, time to surgery, intensive care unit requirement, operation length and length of hospital stay and number of comorbidities were documented. RESULTS: During the study period, 785 patients (262 male, 523 female) were included to study, Overall mortality rate was 37.2 % (292/785). Their age ranged between 65 and 100 years (mean 81). Surgery type Kaplan-Meier cumulative mortality curves suggested no significant difference between four different types of surgery groups (p = 0.064). Transfusion requirement was significantly lower in external fixation group comparing to other groups (p = 0.014). Cox regression analysis showed the number of comorbidities 2 and ≥ 3 (p = 0.0027, p = 0.015), transfusion requirement (p = 0.0001), ASA 4 (p = 0.016) to be significant predictors of mortality. CONCLUSIONS: Transfusion requirement, ASA grade 4 and having more than two comorbidities are risk factors for mortality in geriatric hip fractures. Type of surgical intervention and fracture type had similar mortality rates in our patient population.

Healthcare-associated Gram-negative bloodstream infections: antibiotic resistance and predictors of mortality.

This article describes the prevalence of antibiotic resistance and predictors of mortality for healthcare-associated (HA) Gram-negative bloodstream infections (GN-BSI). In total, 831 cases of HA GN-BSI from 17 intensive care units in different centres in Turkey were included; the all-cause mortality rate was 44%. Carbapenem resistance in Klebsiella pneumoniae was 38%, and the colistin resistance rate was 6%. Multi-variate analysis showed that age >70 years [odds ratio (OR) 2, 95% confidence interval (CI) 1.22-3.51], central venous catheter use (OR 2.1, 95% CI 1.09-4.07), ventilator-associated pneumonia (OR 1.9, 95% CI 1.1-3.16), carbapenem resistance (OR 1.8, 95% CI 1.11-2.95) and APACHE II score (OR 1.1, 95% CI 1.07-1.13) were significantly associated with mortality.

Toward a novel membrane process for organic carbon removal-fate of slowly biodegradable substrate in super fast membrane bioreactor.

The study tested the performance of super fast membrane bioreactor (SFMBR) using starch as a slowly biodegradable substrate, exploring the fate of starch, and the response of the microbial community. SFMBR was operated at extremely low sludge ages of 0.5-2.0 days, with a hydraulic retention time of 1.0 h. Average values for permeate chemical oxygen demand (COD) always remained in the narrow range between 14 and 18 mg/L, regardless of the selected mode of MBR operation at different sludge ages. Soluble COD levels in the reactor were consistently higher than the corresponding permeate COD. Parameters defining process kinetics, determined by model calibration of oxygen uptake rate (OUR) profiles, varied as a function of sludge age. Model simulation of SFMBR performance indicated total removal of hydrolysis products so that permeate COD consisted of residual microbial products. PCR-DGGE experiments revealed significant shifts in the composition of the microbial community imposed by variations in the sludge age, reflecting on corresponding process kinetics.

Importance of Restricting Sportive Activity and Time from Injury to Surgery in Anterior Cruciate Ligament Reconstruction.

OBJECTIVES: It is unclear that how long reconstruction may be delayed before additional intraarticular injuries occur. Our aim was to determine the relationship of time period from injury to surgery with the incidence of meniscal and chondral injuries recorded at the time of surgical treatment for ACL tears. The effect of sportive activity restriction, grade of chondral lesions and their locations were also evaluated. PATIENTS AND METHODS: 213 patients who underwent arthroscopic anterior cruciate ligament reconstruction were evaluated retrospectively. Data were analyzed for association between time period before surgery and patients sportive activity restriction with rates of meniscal and chondral injuries. According to time from initial trauma to surgery less than 12 months grouped as group I (101 patients) and 12 months and longer defined as group II (81 patients). Patients who had surgery before 12 months were divided into groups of smaller time scales (0 to 3 months, 4 to 6 months, 7 to 9 months, 10 to 12 months) to examine the relationships more closely. For sportive activity restriction a functional scale was used that described restricted activities including military training. RESULTS: One hundred eighty-two patients were included to the study. 81 patients restricted sportive activity before surgery. 18 (% 22.2) of these patients had chondral injury [6 (% 33.3) operated before 12 months and 12 (% 66.7) operated after 12 months]. The difference was statistically significant (p=0,005). 81 patients (group II) were operated after 12 months. There were 44 (% 54.3) patients with chondral injury in this group [32 (% 72.7) patients were who continued their sportive activity and 12 (% 27.3) patients who restricted their sportive activity]. The difference was statistically significant (p=0,026). Correlation analysis showed that with increasing time from initial trauma to surgery chondral lesion incidence and grade of these lesions increases (p<0,001, p=0,001). CONCLUSION: The results indicate that the prolonged time from injury to surgery and continuing sportive activity before surgery increases the incidence of the chondral lesions. Also, time limit of 12 month is important to prevent chondral injury in anterior cruciate ligament reconstruction.

Prevalence and risk factors of low bone mineral density in patients with multiple sclerosis.

OBJECTIVES: To determine the prevalence and risk factors of low bone mineral density (BMD) in patients with multiple sclerosis (MS). METHODS: Patients with MS who had undergone a BMD evaluation via dual-energy X-ray absorptiometry (DXA) between January 2010 and December 2013 were included in the study. Descriptive data, BMD values, and risk factors for osteoporosis along with the details regarding MS, such as age at onset, duration of disease, clinical type of MS, expanded disability status scale (EDSS) scores, and lifetime steroid intake were obtained from the medical record database and telephone interview. RESULTS: The study group comprised 67 patients with a mean age of 41.1 ± 10.2 years. Of the patients, 20.9% revealed low BMD for chronological age. Vitamin D insufficiency (25(OH)D < 20  ng/ml) rate was 86.6%. Comorbidity and EDSS scores of patients with low BMD were significantly higher than those of the remaining patients (P = 0.000 and P = 0.015, respectively). Neck BMD was inversely correlated with comorbidity score, disease duration, relapse number, and lifetime steroid intake (r = - 0.270, r = - 0.263, r = - 0.359, and r = - 0.314, respectively). CONCLUSION: The current study revealed that low BMD and vitamin D insufficiency were common in patients with MS. Longer disease duration, higher comorbidity score, and severe disability level led to lower BMD values. In conclusion, it is of paramount importance for clinicians to pay more attention on bone health in MS and to tailor preventative measures meticulously.

Novel indel Mutation in the GDF5 Gene Is Associated with Brachydactyly Type C in a Four-Generation Turkish Family.

Heterozygous loss-of-function mutations of GDF5 are reported to cause hypoplasia/aplasia of certain skeletal elements (brachydactyly), and heterozygous gain-of-function mutations, occurring either on the gene itself or through the loss of its inhibitor noggin, result in joint fusion (symphalangism). We present here the clinical and molecular investigation of a family with disproportionate shortness of the second and third fingers which comprises 9 variably affected members spanning 4 generations. In this study, we performed clinical and radiographical examinations of 2 patients of this family, sequencing of GDF5 and 3D protein modeling of the wildtype and mutated polypeptide to predict the structural alteration. Diagnoses were compatible with familial brachydactyly type C. GDF5 analysis revealed a novel heterozygous in-frame indel mutation (c.803_ 827del25ins25), involving the propeptide domain of GDF5 that alters the number of random coil and beta-strand structures, creating a 1-turn-helix at the mutated site. The mutation described here is the second indel reported in GDF5. The previously published homozygous indel mutation affected the TGF-beta like domain and was associated with Du Pan syndrome. The novel mutation reported here presents further allelic heterogeneity and a probable intrafamilial variable clinical expressivity of GDF5.

Effect of high loading on substrate utilization kinetics and microbial community structure in super fast submerged membrane bioreactor.

The study investigated the effect of high substrate loading on substrate utilization kinetics, and changes inflicted on the composition of the microbial community in a superfast submerged membrane bioreactor. Submerged MBR was sequentially fed with a substrate mixture and acetate; its performance was monitored at steady-state, at extremely low sludge age values of 2.0, 1.0 and 0.5d, all adjusted to a single hydraulic retention time of 8.0 h. Each MBR run was repeated when substrate feeding was increased from 200 mg COD/L to 1000 mg COD/L. Substrate utilization kinetics was altered to significantly lower levels when the MBR was adjusted to higher substrate loadings. Molecular analysis of the biomass revealed that variable process kinetics could be correlated with parallel changes in the composition of the microbial community, mainly by a replacement mechanism, where newer species, better adapted to the new growth conditions, substituted others that are washed out from the system.

Effect of the number of portal area on modified histological activity index of viral hepatitis and histological findings.

AIM: Viral hepatitis is one of the most important causes of chronic hepatitis. Liver biopsy is used to verify clinical diagnosis and to evaluate necroinflammation and fibrosis. Biopsy is the guide for therapy and can be performed also after treatment to assess the effect of therapy on liver. This paper aimed to explore histopathological characteristics of biopsy samples, which had been referred to our department with the clinical diagnosis of chronic viral hepatitis, in reference to Ishak Modified Hepatic Activity Index (IMHAI), as well as to compare inflammatory scores and stages in the groups created according to the number of portal area (PA). MATERIALS AND METHODS: The study included 107 patients that underwent liver biopsy in 2011 being diagnosed with chronic viral hepatitis. Age, gender and type of viral hepatitis were retrospectively reviewed and histological findings such as IMHAI inflammatory score and stage, hepatosteatosis and ground glass hepatocytes were re-assessed by two pathologists. RESULTS: Of the present cases, 97 had chronic hepatitis B, 5 had chronic hepatitis C, and 5 had chronic hepatitis BDThe group with PA number of 2-4 consisted of 8 cases and the group with PA number of 11 and over consisted of 37 cases. CONCLUSION: Statistical analysis performed by comparing IMHAI inflammatory score and stage with PA revealed that score and stage were significantly higher in PA ≥ 11 groups as compared to PA 2-4 group.

Arthroscopic treatment of medial femoral condylar coronal fractures and nonunions.

Nonunion of medial femoral condylar coronal fractures are uncommon. In neglected Hoffa fractures despite nonunion, there is a risk of missing accompanying ligamentous and intra-articular injuries. Neither preoperative clinical examination nor magnetic resonance imaging showed these injuries before arthroscopy. Arthroscopy before internal fixation gives additional information and changes the surgical protocol for these fractures and nonunions.

Mild nasal malformations and parietal foramina caused by homozygous ALX4 mutations.

We report on a boy born to consanguineous parents, who had hypertelorism, a broad nasal bridge, ridge and tip, bifid nasal tip, cleft alae nasi, broad columella, unilateral preauricular tag, shallow labiogingival sulcus, and bilateral large parietal foramina. Cranial MRI revealed a kinked corpus body and small cerebellar vermis. Molecular analysis uncovered a homozygous c.673C > G (p.Q225E) mutation in ALX4 gene. We compare the relatively mild phenotype in the patient to the more marked phenotype described in other patients with homozygous ALX4 mutations, and to the phenotypes in patients with mutations in other ALX genes.

Association of serum sex steroid levels and bone mineral density with CYP17 and CYP19 gene polymorphisms in postmenopausal women in Turkey.

Many clinical conditions, including osteoporosis, are associated with serum levels of sex steroids. Enzymes that regulate rate-limiting steps of steroidogenic pathways, such as CYP17 and CYP19, are also regarded as significant factors that may cause the development of these conditions. We investigated the association of two common polymorphisms, in the promoter region (T→C substitution) of CYP17 and exon 3 (G→A) of CYP19, with bone mineral density (BMD) in the lumbar spine and femoral neck and serum androgen/estradiol, in a case-control study of 172 postmenopausal women aged 62.3 ± 9.6 years (mean ± SD). The CYP17 TC genotype was significantly overrepresented in patients compared to controls, and TC genotype neck T-score and lumbar T-score values were significantly higher in patients compared to controls. CYP17 TC and TT genotype testosterone and DHEA-SO(4) levels were lower in patients compared to controls. All three genotypes of CYP19 had almost the same distribution among patients. The CYP19 AG genotype, however, was most frequent among controls. CYP19 lumbar BMD levels were close to each other among the different genotypes; however, AA and AG genotypes were significantly lower in patients. Testosterone and DHEA-SO(4) levels in the CYP19 GG genotype were higher compared to those of the other genotypes in patients but not in controls. CYP19 GA individuals had lower E(2) levels and lower BMD in controls and patients. Femoral neck BMD and lumbar T-score were also diminished with GA transition. In conclusion, CYP17 and CYP19 gene polymorphisms were found to be associated with osteoporosis in postmenopausal women in Turkey.

Coexistence of neurofibromatosis type 1 and mosaic trisomy 8 in the same patient.

We described trisomy 8 mosaicism in a 6-month-old boy with left corneal leukoma, strabismus, posterior urethral valve, tibial bowing and congenital pseudarthrosis of the tibia (CPT) on graphic of left tibia. The patient also had some minor anomalies such as short philtrum, full everted lower lip, microretrognathia, flexion contracture on his left thumb, deep palmar and plantar creases and three cafe-au-lait macules (CALM) larger than 1 cm on the abdomen. Peripheral blood karyotype analysis of the patient showed 46,XY(10%)/47,XY,+8 (90%)). Mosaic trisomy 8 is a rare syndrome characterized by renal, cardiac, ophthalmologic anomalies, dysmorphic facial features and some skeletal manifestations. When re-evaluated at 2 years of age, his gross motor development was delayed and he also had 12 CALM larger than 1 cm, hence the patient fulfilled NIH diagnostic criteria for Neurofibromatosis type 1 (NF 1) based on the CALM and CPT. A truncating mutation was found through comprehensive NF1 mutation analysis, i.e., c.1019_1020delCT (p.Ser340CysfsX12). Here we report a patient with both mosaic trisomy 8 and NF1, which was not described previously.

Initial maternal meiotic I error leading to the formation of a maternal i(2q) and a paternal i(2p) in a healthy male.

We report on the investigation of the parental origin and mode of formation of the two isochromosomes, i(2p) and i(2q), detected in a healthy adult male. Conventional cytogenetic analysis revealed the proband's lack of structurally normal chromosomes 2, these being replaced by an i(2p) and an i(2q). Investigation of the parental origin of the isochromosomes revealed a paternal origin of the i(2p) chromosome and a maternal origin of the i(2q) chromosome. Thus, the formation of both isochromosomes, or at least of the paternal i(2p), appears to have occurred postzygotically. Interestingly, whilst a paternal isodisomy was observed for the entire 2p, maternal heterodisomy was detected for two segments of 2q, separated by a segment showing isodisomy. The results are indicative of an initial error (non-disjunction or i(2q) formation) concerning the maternal chromosomes 2 during meiosis I, which likely favored the subsequent mitotic recombination event resulting in the presence of two isochromosomes. To the best of our knowledge this is the first case of an initial meiotic error, followed by postzygotic trisomy rescue through the formation of isochromosomes, resulting in a normal phenotype. A prenatal detection, by cytogenetic and molecular analysis, of such chromosome abnormality would have led to the incorrect conclusion of a most likely poor prognosis for the fetus.

A new locus for autosomal recessive non-syndromic mental retardation maps to 1p21.1-p13.3.

Autosomal recessive inheritance of non-syndromic mental retardation (ARNSMR) may account for approximately 25% of all patients with non-specific mental retardation (NSMR). Although many X-linked genes have been identified as a cause of NSMR, only three autosomal genes are known to cause ARNSMR. We present here a large consanguineous Turkish family with four mentally retarded individuals from different branches of the family. Clinical tests showed cognitive impairment but no neurological, skeletal, and biochemical involvements. Genome-wide mapping using Human Mapping 10K Array showed a single positive locus with a parametric LOD score of 4.92 in a region on chromosome 1p21.1-p13.3. Further analyses using polymorphic microsatellite markers defined a 6.6-Mb critical region containing approximately 130 known genes. This locus is the fourth one linked to ARNSMR.