Purpose Evaluation of the clinician’s role in optimal interpretation of clinical exome sequencing (ES) results. Methods Retrospective chart review of the first 155 patients who underwent clinical ES in our Exome Clinic and direct interaction with the ordering geneticist to evaluate the process of interpretation of results. Results The most common primary indication was neurodevelopmental problems (~66%), followed by multiple congenital anomalies (~10%). The overall diagnostic yield was 36% based on sequencing data. After assessment by the medical geneticist, incorporation of detailed phenotypic and molecular data, and utilization of additional diagnostic modalities, the final diagnostic yield was increased to 43%. Seven patients of our cohort were included in initial case series that described novel genetic syndromes, and 23% of patients were involved in subsequent research studies directly related to their results or involved in efforts to move beyond clinical ES for diagnosis. The clinical management was directly altered due to the ES findings in 12% of definitively diagnosed cases. Conclusions Our results emphasize the usefulness of ES, demonstrate the significant role of the medical geneticist in the diagnostic process of patients undergoing ES, and illustrate the benefits of post-analytical diagnostic work-up in solving the “diagnostic odyssey.”

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Background: Mutations in plasma membrane Ca 2ϩ -ATPase (PMCA) isoform 3 and in laminin subunit 1␣ have previously been linked to ataxic phenotypes. Results: A novel PMCA3 missense mutation co-occurring with a compound heterozygous mutation in laminin subunit 1␣ impaired cellular Ca 2ϩ homeostasis. Conclusion:The two mutations could work synergistically to generate the disease phenotype. Significance: A digenic mechanism could be responsible for this case of cerebellar ataxia.

TO THE EDITOR:The precise mapping of chromosomal microdeletion breakpoints by chromosomal microarray analysis provides the opportunity of more accurate genotype-phenotype correlation. Identification of a disease causing gene(s) becomes then possible, especially when the deleted region contains a limited number of genes.Herein, we describe an 8-year and 3-month-old male who was initially evaluated for developmental delay and dysmorphic features. He was born via spontaneous vaginal delivery at 36 weeks of gestation to a 20-year-old G2P1-2, healthy mother and a 22-yearold healthy father; both are of Caucasian descent. The patient's birth weight was 3.8 kg (þ4 SD) and his birth length was 54.6 cm (þ3 SD). The prenatal history was significant for gestational diabetes but there were no perinatal complications. The parents had a 6-year-old daughter and a 9-year-old son who both were healthy.During the first few months of life, the patient had feeding difficulties, gastroesophageal reflux and hypotonia. A gastrostomy tube was placed between 2 and 7 months of age. The patient had left ureteropelvic obstruction, which required pyeloplasty at 6 months of age. At the age of 2 years, he had left small-angle esotropia and amblyopia. Later on, he was diagnosed with bilateral optic atrophy associated with visual motor integration deficit and visual perceptual disorder. He underwent a repair of strabismus on left eye. His audiological evaluation has revealed mild conductive hearing loss. The proband exhibited global developmental delay. He started walking at the age of 3 and forming single words at 4 years of age. Later on, he continued to have abnormal gait and clumsy walking. He had severe fine motor skill abnormalities with special difficulty in handwriting, which led to the diagnosis of graphomotor dysfunction. He had learning difficulties and was diagnosed with attention deficit hyperactivity disorder. He received physical, occupational, speech, and vision therapies.On physical examination, the patient's weight was 25.3 kg (37th centile), his height was 132 cm (62nd centile), and his head circumference was 54 cm (80th centile). He had bilateral epicanthal folds, thin upper lip vermilion, smooth philtrum, mild micrognathia, flaring nares, posteriorly rotated ears ( Fig. 1A and B) and mild pectus carinatum. He had generalized hypotonia and difficulties with heel walking, standing on his tip-toes, rapid alternating movements, and performance of tandem gait. Brain MRI revealed bilateral optic nerve atrophy and small optic chiasm ( Fig. 2A-D). Chromosome analysis of the child showed a normal karyotype. Genome-wide SNP analysis using Affymetrix SNP array 6.0 chip revealed a deletion of 582 kb extending from 92,742,875 to 93,324,350 bp positions (hg18; NCBI Build 36.1, March 2006) within 5q15. Fluorescence in situ hybridization (FISH) studies using RP11-922C8 BAC clone confirmed the deletion in our patient but not in the parents (Fig. 3), indicating that the deletion was de novo. The deleted region included the following genes, FLJ...

Deletion of the short arm of chromosome 5 (5p-) is associated with phenotypic features including a cat-like cry in infancy, dysmorphic facial features, microcephaly, and intellectual disability, and when encompassing a minimal critical region, may be defined as Cri-du-Chat syndrome (CdCS). Most 5p deletions are de novo in origin, and familial cases are often associated with translocation and inversion. Herein, we report three multigenerational families carrying 5p terminal deletions of different size transmitted in an autosomal dominant manner causing variable clinical findings. Terminal 5p deletions and the mode of inheritance were clinically characterized and molecularly analyzed by a combination of microarray and fluorescence in situ hybridization analyses. Shared phenotypic features documented in this cohort included neuropsychiatric findings, poor growth, and dysmorphic facial features. This study supports newly recognized effects of aberrant SEMA5A and CTNND2 dosage on severity of autistic and cognitive phenotypes. Comparative analysis of the breakpoints narrows the critical region for the cat-like cry down to an interval less than 1 Mb encompassing a candidate gene ICE1, which regulates small nuclear RNA transcription. This study also indicates that familial terminal 5p deletion is a rare presentation displaying intra- and inter-familial phenotypic variability, the latter of which may be attributed to size and gene content of the deletion. The observed intra-familial phenotypic heterogeneity suggests that additional modifying elements including genetic and environmental factors may have an impact on the clinical manifestations observed in 5p deletion carriers, and in time, further high resolution studies of 5p deletion breakpoints will continue to aid in defining genotype-phenotype correlations.