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Myelodysplastic syndrome (MDS) is a rare pediatric diagnosis characterized by ineffective hematopoiesis with potential to evolve into acute myelogenous leukemia (AML). In this report, we describe a unique case of a 17-yr-old female with an aggressive course of MDS with excess blasts who was found to have monosomy 7 and aSAMD9germline variant, which has not previously been associated with a MDS phenotype. This case of MDS was extremely rapidly progressing, showing resistance to chemotherapy and stem cell transplant, unfortunately resulting in patient death. It is imperative to further investigate this rare variant to aid in the future care of patients with this variant.

SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.

We performed a cross-sectional, retrospective review of our institution's previous uninformative exome sequencing (ES) results and reanalysis process, and we identified areas of improvement in our genetic testing pipeline. To accomplish this, we performed a detailed chart review of patients who had ES performed from 2013 through 2016 and catalogued data including age, indication for testing, ordering physician specialty, and if a reanalysis was performed. Our final sample included 165 patients with uninformative exome sequencing results, 50 of whom also had reanalysis. Then, descriptive statistics and Fishers exact tests were performed to identify factors associated with whether ES reanalysis had been completed or not. We found that certain factors were more closely associated with a patient having had a reanalysis performed for a normal or uninformative result, like whether the patient had a future appointment within our institution (p = 0.0276). Other factors more closely associated with a patient having reanalysis were if the patient met with a geneticist (p = 0.0018) and/or genetic counselor (p = 0.0027). Other variable such as age, race, and if the patient had a future appointment with their ordering provider were not associated with an increased likelihood of having reanalysis. These results highlight the value of genetics professionals in interpreting complex genetic testing and also identify areas where we may need to improve our current processes. In addition, our results confirm findings from previous studies, implement a basis for other clinics to examine their ES reanalyses pipeline, and allow us to support the call for additional guidelines on ES reanalysis.

Purpose To describe an efficient and effective multiplex screening strategy for sulfatide degradation disorders and mucolipidosis type II/III (MLII/III) using 3 mL of urine. Methods Glycosaminoglycans were analyzed by liquid chromatography-tandem mass spectrometry. Matrix assisted laser desorption/ionization-time of flight tandem mass spectrometry was used to identify free oligosaccharides and identify 22 ceramide trihexosides and 23 sulfatides, which are integrated by 670 calculated ratios. Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu ) was used for post-analytical interpretation of the complex metabolite profile and to aid in the differential diagnosis of abnormal results. Results Multiplex analysis was performed on 25 sulfatiduria case samples and compiled with retrospective data from an additional 15 cases revealing unique patterns of biomarkers for each disorder of sulfatide degradation (MLD, MSD, and Saposin B deficiency) and for MLII/III, thus allowing the formulation of a novel algorithm for the biochemical diagnosis of these disorders. Conclusions Comprehensive and integrated urine screening could be very effective in the initial workup of patients suspected of having a lysosomal disorder as it covers disorders of sulfatide degradation and narrows down the differential diagnosis in patients with elevated glycosaminoglycans.

Primary mitochondrial diseases are a heterogeneous group of disorders that result from defects of the oxidative phosphorylation system of the mitochondria. Often underrecognized, mitochondrial diseases are uncommon (estimated incidence, 1 in 10,000 live births). Mitochondria are double-membrane–bound cytoplasmic organelles whose primary function is to provide energy (ie, adenosine triphosphate [ATP]) from the breakdown of carbohydrates, protein, and lipids by means of the electron transport chain and the oxidative phosphorylation system. The respiratory chain of mitochondria, located in the inner mitochondrial membrane, consists of 5 multimeric protein complexes (complexes I-IV and ATP synthase [complex V]). The structural proteins of these complexes are encoded by both mitochondrial and nuclear genes. Therefore, primary mitochondrial disorders can follow a maternal or mendelian inheritance pattern.

IGF1R-related disorders are associated with intrauterine growth restriction (IUGR), postnatal growth failure, short stature, microcephaly, developmental delay, and dysmorphic facial features. We report a patient who presented to medical genetics at 7 months of age with a history of intrauterine growth restriction (IUGR), poor feeding, mild developmental delays, microcephaly, and dysmorphic facial features. Whole exome sequencing revealed a novel c.1464 T>G (p.Cys488Trp) variant in the IGF1R gene, initially classified as a variation of uncertain significance (VUS). We enrolled the patient in URDC (Undiagnosed Rare Disease Clinic) and performed additional studies including deep phenotyping and familial segregation analysis, which demonstrated that the patient's IGF1R VUS was present in phenotypically similar family members. Furthermore, biochemical testing revealed an elevated serum IGF1 level consistent with abnormal IGF1 receptor function. Work-up resulted in the patient's variant being upgraded from a VUS to likely pathogenic. Our report expands the variant and phenotypic spectrum of IGF1R-related disorders and illustrates benefits and feasibility of reassessing a VUS beyond the initial molecular diagnosis by deep phenotyping, 3D modeling, additional biochemical testing and familial segregation studies through URDC, a multidisciplinary clinical program whose major goal is to end the diagnostic odyssey in patients with rare diseases.

A 7-year-old boy with family history of consanguinity presented with developmental delay and recurrent hemiplegia involving both sides of the body, with variable facial and ocular involvement. Brain MRI showed bilateral striatal necrosis with cystic degeneration and lactate peaks on spectroscopy. Biochemical testing demonstrated mildly elevated lactate and pyruvate. Whole-exome sequencing revealed a novel homozygous pathogenic frameshift mutation in gene TTC19, diagnostic of mitochondrial complex III deficiency.

Lysosomal diseases (LD) comprise a group of approximately 60 hereditary conditions caused by progressive accumulation of metabolites due to defects in lysosomal enzymes and degradation pathways, which lead to a wide range of clinical manifestations. The estimated combined incidence of LD is between 1 in 4000 to 1 in 13,000 live births, with recent data from pilot newborn screening studies showing even higher incidence. We aimed to determine the prevalence of the classical LD and other diseases caused by lysosome-related genes in our cohort of diagnostic odyssey patients. The Individualized Medicine Clinic at Mayo Clinic is increasingly utilizing whole exome sequencing (WES) to determine the genetic etiology of undiagnosed Mendelian disease. From September 2012 to April 2017, WES results from 350 patients with unexplained symptoms were reviewed. Disease-causing variants were identified in MYO6, CLN6, LRBA, KCTD7, and ARSB revealing a genetic diagnosis of a LD in 8 individuals from 5 families. Based on our findings, lysosome-related disorders may be collectively common, reaching up to 1.5% prevalence in a cohort of patients with undiagnosed diseases presenting to a genetics clinic.

Sitosterolemia is an autosomal recessive metabolic disease caused by mutations in ABCG5 or ABCG8 genes which encode for the (ATP)-binding cassette (ABC) transporters that are responsible for the trafficking of xenosterols. Liver involvement is not a recognized manifestation of this disease, and cirrhosis has been reported only once in the medical literature. We describe a fatal case of a 21-year old South Asian male who presented with decompensated cirrhosis, and biochemical abnormalities consistent with sitostero-lemia. Genetic testing showed a homozygous pathogenic mutation in ABCG5, confirming the diagnosis. Sitosterolemia is a rare, but likely under-recognized condition, and a high degree of suspicion is imperative to make the diagnosis. We propose that sitosterolemia should be included in the differential diagnosis for patients with cryptogenic cirrhosis, especially as there are effective oral therapies to treat this condition. Newly diagnosed sitosterolemia patients should undergo a thorough hepatology evaluation and follow-up to evaluate for the presence, development, and progression of any hepatic involvement.

Pediatric acute liver failure (ALF) is life threatening with genetic, immunologic, and environmental etiologies. Approximately half of all cases remain unexplained. Recurrent ALF (RALF) in infants describes repeated episodes of severe liver injury with recovery of hepatic function between crises. We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. ALF episodes are concomitant with fever/infection and not all individuals have complete normalization of liver function testing between episodes. Liver biopsies revealed nonspecific liver damage including fibrosis, steatosis, or mild increases in Kupffer cells. Skeletal imaging revealed abnormalities affecting the vertebrae and pelvis. Dermal fibroblasts showed splice-variant mediated skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay. Fibroblasts also revealed decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux compared to control. RINT1 interacts with NBAS, recently implicated in RALF, and UVRAG, to facilitate Golgi-to-ER retrograde vesicle transport. During nutrient depletion or infection, Golgi-to-ER transport is suppressed and autophagy is promoted through UVRAG regulation by mTOR. Aberrant autophagy has been associated with the development of similar skeletal abnormalities and also with liver disease, suggesting that disruption of these RINT1 functions may explain the liver and skeletal findings. Clarifying the pathomechanism underlying this gene-disease relationship may inform therapeutic opportunities.

Background We describe a patient presenting with pachygyria, epilepsy, developmental delay, short stature, failure to thrive, facial dysmorphisms, and multiple osteochondromas. Methods The patient underwent extensive genetic testing and analysis in an attempt to diagnose the cause of his condition. Clinical testing included metaphase karyotyping, array comparative genomic hybridization, direct sequencing and multiplex ligation-dependent probe amplification and trio-based exome sequencing. Subsequently, research-based whole transcriptome sequencing was conducted to determine whether it might shed light on the undiagnosed phenotype. Results Clinical exome sequencing of patient and parent samples revealed a maternally inherited splice-site variant in the doublecortin (DCX) gene that was classified as likely pathogenic and diagnostic of the patient's neurological phenotype. Clinical array comparative genome hybridization analysis revealed a 16p13.3 deletion that could not be linked to the patient phenotype based on affected genes. Further clinical testing to determine the cause of the patient's multiple osteochondromas was unrevealing despite extensive profiling of the most likely causative genes, EXT1 and EXT2, including mutation screening by direct sequence analysis and multiplex ligation-dependent probe amplification. Whole transcriptome sequencing identified a SAMD12-EXT1 fusion transcript that could have resulted from a chromosomal deletion, leading to the loss of EXT1 function. Re-review of the clinical array comparative genomic hybridization results indicated a possible unreported mosaic deletion affecting the SAMD12 and EXT1 genes that corresponded precisely to the introns predicted to be affected by a fusion-causing deletion. The existence of the mosaic deletion was subsequently confirmed clinically by an increased density copy number array and orthogonal methodologies Conclusions While mosaic mutations and deletions of EXT1 and EXT2 have been reported in the context of multiple osteochondromas, to our knowledge, this is the first time that transcriptomics technologies have been used to diagnose a patient via fusion transcript analysis in the congenital disease setting.

Mucopolysaccharidosis type VI (MPS VI) is a clinically heterogeneous lysosomal disease, which can be divided into 2 main categories on the basis of age of onset and severity of symptoms. The diagnosis of the attenuated form is often delayed given subtle facial features rather than the typical coarse facial features of the classic form. Here, we discuss the difficulties in establishing the diagnosis of MPS VI on the basis of the report of 4 individuals. The most common signs and symptoms in our series were bone abnormalities and hip pain as initial manifestations and cardiac changes detected after follow-up studies. On the basis of our cohort and others worldwide, awareness of attenuated forms of MPS VI should be increased particularly among general practitioners, pediatricians, rheumatologists, orthopedists, ophthalmologists, and cardiologists. Moreover, these health care providers should be aware of the technical aspects involved in the molecular and biochemical diagnosis process so that they are aware how diagnostic errors may occur.

PIK3CA-related overgrowth spectrum (PROS) refers to a group of disorders of segmental overgrowth caused by mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). PROS is an umbrella term that includes several diagnostic entities, some of which were independently described prior to the discovery that PIK3CA mutations were common to all (Keppler-Noreuil et al, Am J Med Genet A 164A(7):1713–1733, 2014; Mirzaa et al, PIK3CA-related segmental overgrowth. In: Pagon et al (ed), GeneReviews® [Internet]. University of Washington, Seattle, pp 1993–2016, 2013). The mutations that cause PROS are typically, but not always, postzygotic, meaning that the mutation is not present in every cell in the body. The resulting mosaicism causes some of the phenotypic variation, although specific PIK3CA genotypes also contribute. The PROS diagnostic entities (Keppler-Noreuil et al, Am J Med Genet A 167A(2):287–295, 2015) include: Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal (CLOVES) syndrome Fibroadipose hyperplasia or overgrowth (FAO)/hemihyperplasia multiple lipomatosis (HHML) Klippel-Trenaunay syndrome (KTS) Megalencephaly-capillary malformation syndrome (MCAP syndrome) Hemimegalencephaly (HMEG) and dysplastic megalencephaly (DMEG) Isolated macrodactyly Isolated lymphatic malformations (LM) Facial infiltrating lipomatosis Focal cortical dysplasia (FCD)

Item does not contain fulltext N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Background Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is an autosomal-dominant disorder characterised by lentigines, EKG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation and deafness. There is significant clinical overlap between NSML and other disorders that result from dysregulated rat sarcoma/mitogen-activated protein kinase pathway (RASopathies). Except for neurofibromatosis type 1, other RASopathies are not known to be typically associated with neurogenic tumours. Methods and results We evaluated patients from three families with pigmentary skin lesions, progressive neuropathy, enlarged nerves, massive burden of paraspinal tumours (neurofibroma was confirmed in one patient) and a clinical diagnosis of NSML. All patients had a mutation in the protein tyrosine phosphatase catalytic domain of the PTPN11 gene; two unrelated patients had the p.Thr468Met mutation, while the family consisting of two affected individuals harboured the p.Thr279Cys mutation. Molecular analysis performed on hypertrophic nerve tissue did not disclose a second somatic hit in NF1, PTPN11, NF2 or SMARCB1 genes. Conclusions Neurogenic tumours and hypertrophic neuropathy are unusual complications of NSML and may be an under-recognised manifestation that would warrant surveillance. Our observation may also have implications for other disorders caused by RAS-pathway dysregulation.

Whole-exome sequencing (WES) is being used clinically to diagnose rare Mendelian disorders, especially when standard tests have failed. The diagnostic yield from WES is reported to be ∼15-30%; however, data regarding the clinical utility and interpretative challenges from the clinician's perspective are lacking. Here, we present a series of the first 6 unselected consecutive cases seen over a period of 6 months where WES was employed in clinical labs via trio-based testing (proband and parents). While we do not discount the value of WES in the clinical setting, our cases and experience illustrate the significant clinical challenges of WES, even when a diagnosis may be achieved.

We report a 9-year-old Chinese girl with congenital thrombotic thrombocytopenic purpura found to be a compound heterozygote for 2 pathogenic variants in the ADAMTS13 gene, including a novel variation. The girl suffered from recurrent, life-threatening episodes of thrombocytopenia and hemolysis, and laboratory testing showed ADAMST13 enzyme activity of5%. Sequencing of the ADAMTS13 gene revealed a previously reported missense variant, c.1787CT (p.Ala596Val), and a novel duplication defined as c.1007_1025dup19 (p.Asp343Leufs*53); the duplication is predicted to result in a premature stop codon and protein truncation. We propose that this novel variant is partly responsible for the patient's early-onset and severe phenotype.

ACTB encodes the β-actin, and pathogenic variations in this gene have typically been associated with Baraitser-Winter cerebrofrontofacial syndrome, a congenital malformation syndrome characterized by short stature, craniofacial anomalies, and cerebral anomalies. Here, we describe the third case with the p.Arg183Trp variant in ACTB causing juvenile-onset dystonia. Our patient has severe, intractable dystonia, developmental delay, and sensorineural hearing loss, besides hyperintensities in the caudate nuclei and putamen on the brain MRI, which is a distinct but overlapping phenotype with the previously reported case of identical twins with the same alteration in ACTB.

We report an 8-month-old infant with decreased consciousness after a febrile episode and reduced oral intake. He was profoundly acidotic but his lactate was normal. Serum triglycerides were markedly elevated and HDL cholesterol was very low. The urine organic acid analysis during the acute episode revealed a complex pattern of relative hypoketotic dicarboxylic aciduria, suggestive of a potential fatty acid oxidation disorder. MRI showed extensive brain abnormalities concerning for a primary energy deficiency. Whole exome sequencing revealed heterozygotic HMGCS2 variants. HMGCS2 encodes mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase-2 (HMGCS2), which catalyzes the irreversible and rate-limiting reaction of ketogenesis in the mitochondrial matrix. Autosomal recessive HMG-CoA synthase deficiency (HMGCS2D) is characterized by hypoketotic hypoglycemia, vomiting, lethargy, and hepatomegaly after periods of prolonged fasting or illness. A retrospective analysis of the urine organic acid analysis identified 4-hydrox-6-methyl-2-pyrone, a recently reported putative biomarker of HMGCS2D. There was also a relative elevation of plasma acetylcarnitine as previously reported in one case. Our patient highlights a unique presentation of HMGCS2D caused by novel variants in HMGCS2. This is the first report of HMGCS2D with a significantly elevated triglyceride level and decreased HDL cholesterol level at presentation. Given this, we suggest that HMGCS2D should be considered in the differential diagnosis when hypertriglyceridemia, or low HDL cholesterol levels are seen in a child who presents with acidosis, mild ketosis, and mental status changes after illness or prolonged fasting. Although HMGCS2D is a rare disorder with nonspecific symptoms, with the advent of next-generation sequencing, and the recognition of novel biochemical biomarkers, the incidence of this condition may become better understood.

Endurance training has been associated with increased orthostatic intolerance. The purpose of the present study was to test the hypothesis that endurance training reduces renal vasoconstriction to orthostatic stress. Blood pressure, heart rate, and renal blood flow velocity were measured during a 25-min 60 degrees head-up tilt (HUT) test before and after 8 wk of endurance training in eight healthy sedentary subjects (26 +/- 1 yrs). Training elicited a 21 +/- 3% increase in peak oxygen uptake (V(O(2)peak)) and a reduction in heart rate at rest of 8 +/- 2 beats/min. During HUT, heart rate progressively increased (approximately 20 beats/min) over the 25-min HUT trial both before and after training. Systolic arterial blood pressure during HUT was unchanged with training, whereas diastolic arterial blood pressure was lower at the end of HUT after training. Before training renal blood flow velocity (Delta14 +/- 5 cm/s) and renal vascular conductance (Delta22 +/- 7%) decreased during HUT, whereas after training renal blood flow velocity (Delta2 +/- 5 cm/s) and renal vascular conductance (Delta1 +/- 12%) did not change significantly during HUT. Renal blood flow velocity and vascular conductance responses to HUT did not change in control subjects during the 8-wk period. These results demonstrate that endurance training reduces renal vasoconstriction during an orthostatic challenge and may contribute to training-induced orthostatic intolerance.

Engagement of the otolith organs elicits differential activation of sympathetic nerve activity and vascular responses to muscle and skin in humans. Additionally, aging attenuates the otolith organ-mediated increases in muscle sympathetic nerve activity in older adults. In this study, we hypothesized that 1) the vestibulosympathetic reflex (VSR) would elicit visceral vascular vasoconstriction and 2) visceral vascular response to the VSR would be attenuated in older subjects compared with young. To test these hypotheses, heart rate, mean arterial blood pressure, and renal, celiac trunk, and superior mesenteric arterial blood velocity (Doppler ultrasound) were measured in 22 young (25 ± 1 yr) and 18 older (65 ± 2 yr) healthy subjects during head-down rotation (HDR), which selectively activates the otolith organs. Mean arterial pressure and heart rate did not change from baseline during HDR in young or older subjects. Renal blood velocity (Δ −2 ± 1 cm/s) and vascular conductance (Δ −0.03 ± 0.01 cm·s−1·mmHg−1) significantly decreased from baseline during HDR ( P < 0.05) in young subjects. In contrast, renal blood velocity and conductance did not change in older subjects (Δ −0.2 ± 1 cm/s and Δ0.02 ± 0.08 mmHg·cm−1·s−1, respectively) during HDR. Superior mesenteric and celiac blood velocity and vascular conductance did not change in response to HDR in either the young or older subjects. These data suggest that renal vasoconstriction occurs during otolith organ activation in young but not older humans. Together with our previous studies, we conclude that the VSR elicits a diverse patterning of sympathetic outflow that results in heterogeneous vascular responses in humans and that these responses are significantly attenuated in older humans.

Lysosomes are membrane-bound organelles that degrade various macromolecules. Lysosomal storage diseases are a clinically, enzymatically, and genetically heterogeneous group of disorders resulting from intracellular accumulation of substrates. Mechanisms of lysosomal storage disorders include 1) primary deficiency of specific hydrolases; 2) defects in activator proteins required for enzyme-substrate interactions in posttranslational modification of enzymes or in transport of the substrate from lysosomes; and 3) abnormalities of fusion between autophagic vacuoles and lysosomes. Substrate accumulation is slowly progressive, leading to considerable morbidity and mortality.

PURPOSE. To determine the extent of retinal ganglion cell loss and morphologic abnormalities in surviving ganglion cells in Ins2 Akita/+ diabetic mice. METHODS. Mice that expressed cyan fluorescent protein (CFP) or yellow fluorescent protein (YFP) reporter genes under the transcriptional control of the Thyl promoter were crossed with Ins2 Akita/+ mice. After 3 months of diabetes, the number and morphology of retinal ganglion cells was analyzed by confocal microscopy. The number of CFP-positive retinal ganglion cells was quantified in retinas of Ins2 Akita/+ Thyl-CFP mice. The morphology of surviving cells was examined, and dendritic density was quantified in Ins2 Akita/+ Thyl-YFP mice by using the Sholl analysis. RESULTS. Thyl-CFP expression was limited to retinal ganglion cell bodies. There was a 16.4% reduction in the density of CFP-positive ganglion cells in the peripheral retina of Ins2 Akita/+ mice compared with wild-type control retinas (P < 0.017), but no significant change in the central retina. Thyl-YFP expression occurred throughout the entire structure of a smaller number of cells, including their soma, axons, and dendrites. Six different morphologic clusters of cells were identified in the mouse retinas. The structure of dendrites of ON-type retinal ganglion cells was affected by diabetes, having 32.4% more dendritic terminals (P < 0.05), 18.6% increase in total dendrite length (P < 0.05), and 15.3% greater dendritic density compared with control retinas, measured by Scholl analysis. Abnormal swelling on somas, axons, and dendrites were noted in all subtypes of ganglion cells including those expressing melanopsin. CONCLUSIONS. The data show that retinal ganglion cells are lost from the peripheral retina of mice within the first 3 months of diabetes and that the dendrites of surviving large ON-type cells undergo morphologic changes. These abnormalities may explain some of the early anomalies in visual function induced by diabetes.