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Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

The transition from pediatric- to adult-based health care is known to be difficult, particularly for individuals with chronic illness and/or disabilities, including many people with genetic diagnoses. This chapter focuses on several of the issues that add to the complexity of this challenging period. It is important for medical providers to be aware of changes to health insurance coverage, be versed in the options and resources available to facilitate vocations upon high school graduation, and understand the legal implications of the existing options for medical decision-making. Additionally, there are many psychosocial considerations that can greatly impact healthcare delivery and affect health and wellness. Given these challenges, it is important to have evidence-based processes and practices in place to facilitate transition planning and improve related outcomes.

Cardiovascular manifestations of Marfan syndrome are associated with increased mortality, especially in the pediatric population. Early recognition is critical to long-term management. We present two cases of genetically defined “classical” Marfan syndrome presenting with severe infantile aortic root dilatation among siblings and discuss options for therapy.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care. ispartof: GENETICS IN MEDICINE vol:21 issue:4 pages:867-876 ispartof: location:United States status: published

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Catel-Manzke syndrome is a rare autosomal recessive disorder characterized by Pierre Robin sequence with hyperphalangy and clinodactyly of the index finger. Recently, homozygous or compound heterozygous pathogenic variants in TGDS have been discovered to cause Catel-Manzke syndrome. Here, we describe a 12-month-old male with molecularly confirmed Catel-Manzke syndrome who presented with Pierre Robin sequence (but without cleft palate) and hyperphalangy, and we compare his phenotype with the seven previously described patients with pathogenic variants in TGDS. Our patient is on the severe end of the phenotypic spectrum, presenting with respiratory complications and failure to thrive. Furthermore, our finding of a homozygous p.Ala100Ser pathogenic variant in our patient supports that it is a common mutation in Catel-Manzke syndrome.

Neural crest cells (NCCs) are physically responsible for craniofacial skeleton formation, pharyngeal arch artery remodeling and cardiac outflow tract septation during vertebrate development. Cdc42 (cell division cycle 42) is a Rho family small GTP-binding protein that works as a molecular switch to regulate cytoskeleton remodeling and the establishment of cell polarity. To investigate the role of Cdc42 in NCCs during embryonic development, we deleted Cdc42 in NCCs by crossing Cdc42 flox mice with Wnt1-cre mice. We found that the inactivation of Cdc42 in NCCs caused embryonic lethality with craniofacial deformities and cardiovascular developmental defects. Specifically, Cdc42 NCC knockout embryos showed fully penetrant cleft lips and short snouts. Alcian Blue and Alizarin Red staining of the cranium exhibited an unfused nasal capsule and palatine in the mutant embryos. India ink intracardiac injection analysis displayed a spectrum of cardiovascular developmental defects, including persistent truncus arteriosus, hypomorphic pulmonary arteries, interrupted aortic arches, and right-sided aortic arches. To explore the underlying mechanisms of Cdc42 in the formation of the great blood vessels, we generated Wnt1Cre-Cdc42-Rosa26 reporter mice. By beta-galactosidase staining, a subpopulation of Cdc42-null NCCs was observed halting in their migration midway from the pharyngeal arches to the conotruncal cushions. Phalloidin staining revealed dispersed, shorter and disoriented stress fibers in Cdc42-null NCCs. Finally, we demonstrated that the inactivation of Cdc42 in NCCs impaired bone morphogenetic protein 2 (BMP2)-induced NCC cytoskeleton remodeling and migration. In summary, our results demonstrate that Cdc42 plays an essential role in NCC migration, and inactivation of Cdc42 in NCCs impairs craniofacial and cardiovascular development in mice.

In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5′ untranslated region (5′UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.–14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation.

The purpose of our study is to familiarize the reader with genetic disorders commonly seen in adults and identify challenges and barriers that limit provision of services. We conducted a retrospective chart analysis of patients seen in the adult Genetics clinics from January 2004 to December 2010 in a metropolitan medical center consisting of an academic private clinic and a county hospital clinic. During the study period, a total of 1,552 patients (n = 1,108 private clinic patients; n = 444 county clinic patients) were evaluated and managed. Of these, 790 and 280 were new patient visits at the private clinic and county clinic, respectively. Approximately 35% (374/1,070) of new patients were seen for cancer-related indications, while neurological indications accounted for approximately 14% (153/1,070) in both clinics. Cardiology-related indications accounted for approximately 13% (145/1,070) of patients, followed closely by chromosomal and syndromic indications for which almost 9% (96/1,070) of new patients were seen. Approximately 8% (90/1,070) of new patients were seen for musculoskeletal indications. We saw increased clinic growth during the study period and found that the most common indications for referral are: (1) Personal/family history of cancer (2) neurological (3) cardiovascular (CV) (4) chromosomal/syndromic and (5) musculoskeletal. A number of challenges were identified, including coordination of services, feasibility of testing, and an overall higher complexity of care with increased clinic scheduling time requirements. Through this review, we demonstrate the demand for adult genetics services and propose some guidelines to address the challenges of management in the adult genetics patient population.

Introduction Pathogenic mutations in the OPA1 gene are the most common identifiable cause of autosomal dominant optic atrophy (DOA), which is characterized by selective retinal ganglion cell loss, a distinctive pattern of temporal pallor of the optic nerve and a typical color vision deficit, with variable effects on visual acuity. Haploinsufficiency has been suggested as the major pathogenic mechanism for DOA. Here we present two siblings with severe ataxia, hypotonia, gastrointestinal dysmotility, dysphagia, and severe, early-onset optic atrophy who were found to be compound heterozygotes for two pathogenic OPA1 mutations. This example expands the clinical phenotype of OPA1-associated disorders and provides additional evidence for semi-dominant inheritance. Methods and results Molecular analysis of the OPA1 gene in this family by Sanger sequencing revealed compound heterozygosity for two mutations in trans configuration, a p.I382M missense mutation and a p.V903GfsX3 frameshift deletion in both affected siblings. Electron microscopy of a skeletal muscle biopsy of the older sibling revealed dense osmiophilic bodies within the mitochondria. Mitochondrial DNA (mtDNA) content was within normal limits, and electron transport chain analysis showed no deficiencies of the mitochondrial respiratory chain enzymes. Multiple mtDNA deletions were not found. Conclusion Compound heterozygosity of pathogenic OPA1 mutations may cause severe neuromuscular phenotypes in addition to early-onset optic atrophy. While a role for OPA1 in mtDNA maintenance has been discussed, compound biallelic pathogenic OPA1 mutations in our patients did not result in altered mtDNA copy number, mtDNA deletions, or deficiencies of the electron transport chain, despite the severe clinical phenotype.

TO THE EDITOR: Most cases of Edwards syndrome result from an extra copy of chromosome 18 (Trisomy 18) [Edwards et al., 1960], however, a small fraction of individuals have unbalanced translocations or isochromosome 18q (i(18q)) [Bass et al., 1979; Froster-Iskenius et al., 1984], reviewed in Bugge et al. [2004]. The observation of i(18q) generally indicates a deletion of the entire short arm of chromosome 18 and a gain of the entire long arm; however, we have identified two unique cases in which cytogenetically apparent isochromosomes 18q were in fact complex rearrangements involving portions of both 18p and 18q. In one case, chromosome studies were initially performed in the newborn period, and low resolution banding failed to identify the complex nature of the rearrangement. In the second case, array CGH initially identified the complex rearrangement, however, follow up chromosome studies revealed an isochromosome-like appearance of the derivative 18. Thus, the results presented here demonstrate that patients with isochromosomes identified by conventional chromosome analysis could benefit from more detailed molecular cytogenetic studies such as FISH and array CGH. The first patient was delivered at 33.5 weeks gestation by cesarean section for abnormalities in fetal heart monitoring. A routine fetal ultrasound revealed an enlarged right atrium, and a fetal echocardiogram revealed a mobile mass in the left ventricular outlet. Birth weight was 1,353 g and head circumference was 23 cm, both well below the 5th percentile for gestational age. Features included prominent occiput with a large posterior fontanelle, posteriorly rotated ears, clenched hands, hypoplasia of the nails, a short sternum, and mild rocker-bottom feet. An echocardiogram revealed multiple abnormalities, including a large patent ductus arteriosus, a large muscular ventricular septal defect, and aneurismal redundant tricuspid valve tissue. G-tube/Nissen fundoplication, bilateral inguinal hernia repair, and tracheostomy placement were performed at 4½ months of age. At 4 years of age, the child was nonverbal and could sit but not crawl or walk. He weighed 13.1 kg and received a mixture of G-tube feeds and oral feeds. He no longer required mechanical ventilation; however, he had a tracheostomy in place and required oxygen at night. The initial low-resolution GTG-banded chromosome analysis performed in the newborn period identified an abnormal male karyotype with one normal chromosome 18 and one apparent isochromosome 18q, consistent with the clinical diagnosis of Edwards syndrome (Fig. 1a). Follow-up high-resolution studies of the maternal chromosomes were performed which identified a pericentric inversion of one chromosome 18 between bands 18p11.31 and 18q12.2 (Fig. 1b). Given this result, a repeat high-resolution chromosome analysis combined with FISH studies was performed on Patient 1, which revealed that the child had in fact one normal chromosome 18 and one complex chromosome 18 made up of one q arm and one arm consisting of the proximal portion of 18p from 18p11.31 to the centromere and the distal portion of 18q from 18q12.2 to qter (Fig. 1c,e). Based on this data, the karyotype was redefined as 46,XY,rec(18)dup(18q)inv(18)(p11.31q12.2). Following a genetics consultation, it was noted that the mother had 5 previous pregnancies, 4 of which resulted in spontaneous abortions and 1 that produced a child with dextrocardia and congenital diaphragmatic hernia who died in the first 24 hr of life. Karyotype analysis on that child revealed an abnormal chromosome 18, reported as 46,XY,i(18)(q10) by an outside lab. A third child (sibling 2) has since been born following an abnormal prenatal chromosome analysis which revealed the same recombinant chromosome 18 as the proband (Fig. 1d). FIG. 1 Partial karyotypes and ideograms of the three family members included in Case 1. Red and green highlighted areas on the ideograms correspond to FISH probes in (e). a: Initial low-resolution chromosomes 18 from Patient 1. b: Maternal chromosomes 18 showing ... The second patient was born prematurely at 34 weeks gestation to a G1P0→1 mother via cesarean. Birth weight was 1,490 g (10th centile) and head circumference was 29.5 cm (10th–25th centile). Clinical features included a triangular facies, prominence of the forehead, intact high-arched palate, malformed ears with incomplete folding of bilateral helices, abnormal tragus and a cup-shaped right pinna. She had a III/VI harsh holosystolic cardiac murmur, patent foramen ovale, atrial septal defect and a large subaortic ventriculoseptal defect. The digits were without the typical overlapping seen in complete Trisomy 18 patients. A weak suck was noted, and swallow studies demonstrated moderate-to-severe dysphagia with nasopharyngeal aspiration. The perinatal course was complicated by prematurity, intrauterine growth retardation, respiratory distress, periodic breathing, hyperbilirubinemia, metabolic acidosis, hyponatremia, hypokalemia, and feeding intolerance. At 3 months of age, the child passed away due to complications related to congestive heart failure. Array-based comparative genomic hybridization (array CGH) analysis was performed at 40 days of age and revealed a gain in copy number in the subtelomeric region of the short arm of chromosome 18 at band 18p11.32 to18p11.31 (Fig. 2a,b). The duplication spanned a minimum of 4.7 Mb and a maximum of 4.8 Mb and was confirmed by FISH analysis. Additionally, there was a gain in copy number in the long arm of chromosome 18 at band 18q12.3 to 18q23, encompassing a segment of 38.7 Mb in size. GTG-banded chromosome analysis was subsequently performed to further characterize the chromosomal rearrangements. This analysis revealed the presence of one normal chromosome 18 and one apparent isochromosome 18q which, based on array CGH data, was in fact a derivative chromosome 18 consists of a duplication of band 18p11.32 to 18p11.31 and a duplication of band 18q12.3 to 18q23. FISH studies using probes specific to the regions 18p11.31, 18q12.3, 18q23, and 18cen confirmed the inverted nature of the dup (18p) and the dup (18q) (Fig. 3b–d). Based on this data, the infant’s karyotype was designated according to ISCN 2009 and the hg18 build of the human genome as 46,XX,der-(18)dup(18)(p11.32p11.31)dup(18)(q12.3q23).nuc ish 18p11. 31(RP11-838N2×3). arr 18p11.32p11.31(121700–4832613)×3, 18q12.3q23(37401561–76103255)×3. Paternal partial chromosome analysis showed no evidence of a rearrangement involving chromosome 18; however, the maternal sample was not available for analysis. FIG. 2 Array CGH analysis of Patient 2. a: Whole genome plot (left) depicting gain in copy number at 18p11.32-p11.31 and 18q12.3-q23. The enlarged segment of both 18p11.32-p11.31 (~5 Mb) and 18q12.3-q23 (38.7 Mb) is shown on the right. Each point represents ... FIG. 3 Cytogenetic and FISH analyses of Patient 2. a: Partial karyotype showing the normal chromosome 18 and the derivative 18 (arrows). b: Interphase FISH using probes RP11-183C12 (18p11.31, green, 4.4–4.6 Mb) and RP11-838N2 (18p11.31, red, 3.3–3.5 ... In summary, the cases presented here demonstrate the extent to which molecular studies can further elucidate chromosomal abnormalities that are detected by karyotype. In the first case, molecular studies allowed for the identification of a recombinant chromosome 18 found in both the proband (Patient 1) and his sibling, resulting from a maternal inversion (Fig. 1). This is consistent with previously reported chromosome 18 rearrangements in individuals born to normal parents, one of whom carries a pericentric inversion of chromosome 18 [Vianna-Morgante et al., 1976]. In the second case (Patient 2), array CGH identified multiple duplications of chromosome 18 material, and FISH studies revealed the nature of the complex rearrangement (Figs. 2 and ​and3).3). It is important to note that, cytogenetically, both patients had an apparent i(18q). Low-resolution GTG-banded chromosome analysis, which is common for newborn blood specimens or prenatal specimens, could easily have failed to detect these complex rearrangements. Given their cryptic nature, it is easy to predict that similar rearrangements may be more common in ‘‘apparent’’ isochromosomes than previously appreciated. For this reason, cases of i(18q) and other isochromosomes should be interpreted with caution, especially in the case of prenatal chromosome analysis when band resolution is low. Detailed molecular studies such as array CGH and FISH analysis may provide valuable information about the composition of an apparent isochromosome and should be used whenever possible.

Pheochromocytoma is an infrequent but well-acknowledged primary cause of malignant hypertension in pregnancy. Although the majority of pheochromocytomas are sporadic, those that present as bilateral or multifocal tumors may be a manifestation of a rare cancer susceptibility syndrome, such as Von Hippel-Lindau (VHL). Gravidae with unrecognized pheochromocytoma are at risk for recurrent paroxysmal hypertensive crises with ensuant maternal and fetal risks. To further illustrate the challenges of management of pheochromocytoma and VHL in pregnancy, we present two illustrative cases. In the first, a multigravida presented with an intrauterine fetal demise and malignant hypertension and a concurrent diagnosis of bilateral pheochromocytomas. A missense mutation in exon 3 of the VHL gene was identified, confirming the diagnosis of VHL type 2C. In the second case, a multigravida with a prior diagnosis of VHL syndrome but sporadic follow-up underwent renal and adrenal imaging surveillance as part of her prenatal care. Although she was normotensive and clinically asymptomatic, such imaging enabled the detection of bilateral pheochromocytomas. In summary, in this report we discuss our management in gravidae with pheochromocytoma and VHL, emphasizing current recommendations pertaining to obstetric management, genetic testing, and long-term follow-up.

Skeletal abnormalities are a recognized component of Neurofibromatosis type I (NF1) but a generalized metabolic bone defect in NF1 has not been fully characterized thus far. The purpose of this study was to characterize at the densitometric, biochemical and pathological level the bone involvement in NF1 patients. Using dual energy X-ray absorptiometry (DXA) we analyzed bone status in 73 unselected NF1 subjects, 26 males and 47 females, mainly children and adolescents (mean age: 16.6 years). In a subgroup of subjects with low bone mass, we measured indices of calcium-phosphate metabolism, bone turnover, and bone density before and after vitamin D and calcium treatment. We found statistically significant and generalized reduction in bone mass with the mean lumbar bone mineral density (BMD) z-score being -1.38+/-1.05 (CI 95% -1.62 to -1.13), and whole body bone mineral content (BMC) z-score -0.61+/-1.19 (CI 95% -0.94 to -0.29), both significantly reduced compared to normal controls (p

Purpose: Williams-Beuren syndrome is among the most well-characterized microdeletion syndromes, caused by recurrent de novo microdeletions at 7q11.23 mediated by nonallelic homologous recombination between low copy repeats flanking this critical region. However, the clinical phenotype associated with reciprocal microduplication of this genomic region is less well described. We investigated the molecular, clinical, neurodevelopmental, and behavioral features of seven patients with dup(7)(q11.23), including two children who inherited the microduplication from one of their parents, to more fully characterize this emerging microduplication syndrome. Methods: Patients were identified by array-based comparative genomic hybridization. Clinical examinations were performed on seven affected probands, and detailed cognitive and behavioral evaluations were carried out on four of the affected probands. Results: Our findings confirm initial reports of speech delay seen in patients with dup(7)(q11.23) and further delineate and expand the phenotypic spectrum of this condition to include communication, social interactions, and repetitive interests that are often observed in individuals diagnosed with autism spectrum disorders. Conclusions: Array-based comparative genomic hybridization is a powerful means of detecting genomic imbalances and identifying molecular etiologies in the clinic setting, including genomic disorders such as Williams-Beuren syndrome and dup(7)(q11.23). We propose that dup(7)(q11.23) syndrome may be as frequent as Williams-Beuren syndrome and a previously unrecognized cause of language delay and behavioral abnormalities. Indeed, these individuals may first be referred for evaluation of autism, even if they do not ultimately meet diagnostic criteria for an autism spectrum disorder.

Optic pathway tumors (OPT) occur in about 15% of individuals with Neurofibromatosis Type 1 (NF1) and may effect substantial visual loss. Because their growth is not predictable at the time of discovery, neuroimaging for OPT in asymptomatic NF1 patients remains controversial. We evaluated the outcomes of systematic screening by both MRI and ophthalmic examinations for OPT in young children with NF1 seen at multi-disciplinary clinics for Neurofibromatosis and Genetics at one institution between 1996 and 2001. We report on 84 children who presented with NF1 under age 6 years, of whom 13 children presented with either known OPT or abnormal MRI findings and 11 children had OPTs identified by neuroimaging, including two children with abnormal eye examinations at presentation (one with strabismus and one with optic atrophy). Nine OPTs were detected in asymptomatic subjects with normal ophthalmic examinations. Three children with chiasmal lesions enlarging on subsequent MRI were treated with carboplatin and vincristine. After treatment, the vision in each involved eye was intact. In contrast, the 13 children with OPT diagnosed outside of screening guidelines included five children with substantial visual loss. Our observations suggest that early recognition of NF1 promotes appropriate surveillance and allows early intervention to reduce complications of OPT. This analysis supports prospective studies to compare the outcomes of systematic screening with neuroimaging to screening with ophthalmic examinations alone in children with NF1. © 2004 Wiley-Liss, Inc.

Hereditary nonpolyposis colon cancer (HNPCC, Online Mendelian Inheritance in Man (OMIM) 114500) is an autosomal dominant disorder that is genetically heterogeneous because of underlying mutations in mismatch repair genes, primarily MLH1, MSH2, and MSH6. One challenge to correctly diagnosing HNPCC is that the large size of the causative genes makes identification of mutations both labor intensive and expensive. We evaluated the usefulness of denaturing high performance liquid chromatography (DHPLC) for scanning mismatch repair genes (MLH1, MSH2, and MSH6) for point mutations, small deletions, and insertions. Our assay consisted of 51 sets of primers designed to amplify all exons of these genes. All polymerase chain reaction reactions were amplified simultaneously using the same reaction conditions in a 96-well format. The amplified products were analyzed by DHPLC across a range of optimum temperatures for partial fragment denaturation based on the melting profile of each specific fragment. DNA specimens from 23 previously studied HNPCC patients were analyzed by DHPLC, and all mutations were correctly identified and confirmed by sequence analysis. Here, we present our validation studies of the DHPLC platform for HNPCC mutation analysis and compare its merits with other scanning technologies. This approach provides greater sensitivity and more directed molecular analysis for clinical testing in HNPCC.

Heterozygous mutations in one of the DNA mismatch repair genes cause hereditary nonpolyposis colorectal cancer (MIM114500). Turcot syndrome (MIM276300) has been described as the association of central nervous system malignant tumors and familial colorectal cancer and has been reported to be both a dominant and recessive disorder. Homozygous and compound heterozygous mutations in APC, MLH1, MSH2, and PMS2 genes have been reported in five families. Here we describe a nonconsanguineous Pakistani family, including a son with lymphoma and colorectal cancer diagnosed at ages 5 and 8, respectively, and an 8-year-old daughter with glioblastoma multiforme. Both children had features of neurofibromatosis type 1 including atypical café au lait spots and axillary freckling without a family history consistent with neurofibromatosis type 1, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer. Mutational analysis was done for MLH1, MSH2, and MSH6 using denaturing high-performance liquid chromatography and sequencing of a blood sample from the daughter. A novel homozygous single base insertion mutation was identified (3634insT) resulting in a premature stop at codon 1,223 in exon 7 of the MSH6 gene. Both parents were found to be heterozygous for the 3634insT mutation. Microsatellite instability testing showed instability in the glioblastoma sample. We report here the first identification of a homozygous mutation in MSH6 in a family with childhood-onset brain tumor, lymphoma, colorectal cancer, and neurofibromatosis type 1 phenotype. Our findings support a role for MSH6 in Turcot syndrome and are consistent with an autosomal recessive mode of inheritance.

An 11-year-old boy was evaluated for progressive ataxia, cognitive deterioration, and ophthalmoplegia. The child initially presented with abnormal eye movements at the age of 2 months and was noted to have developmental delay at 6 months. At the age of 7 years, he developed ataxia and cognitive impairment, and subsequently manifested dysphagia and incontinence. The pertinent family history included gait difficulty in the paternal grandmother. At the age of 11, his general physical examination was normal. On neurological examination, he had bilateral external ophthalmoplegia, ataxic dysarthria, dysmetria and tremor in the upper extremities, and marked gait ataxia. An ophthalmological evaluation showed no evidence of pigmentary retinopathy. Brain MRI demonstrated cerebellar, brainstem, and cerebral atrophy. An ataxia panel showed 62 repeats in one allele of the SCA2 gene. Most cases of spinocerebellar ataxia type 2 (SCA2) present between 20 years and 40 years, and affected individuals typically have between 34 and 57 CAG repeats. Neonatal cases of SCA2 have been reported in individuals with over 200 CAG repeats. Childhood SCA2 has been reported previously in two patients but not described clinically. This case broadens the spectrum of the clinical features of infantile-onset SCA2 and highlights the importance of considering this diagnosis in infants and children.

Background/Aims Family relationship data in the Scott & White Virtual Data Warehouse (VDW) gathered from multiple sources across the institution is a rich resource that provides an opportunity to study patterns of inherited disease and the ability to evaluate the efficacy of targeted screening strategies. In an integrated healthcare delivery system, linkage of the parent and child (family) electronic health records (EHR) provides an opportunity to improve outcomes by implementing proactive/preventative screening and/ or treatment in offspring. Our study focuses on how linkage of the parent/ child EHR can be used to identifying youth at risk for a number of autosomal dominant inherited diseases.