Development of retinal structure and function is controlled by cell type-specific transcription factors and widely expressed co-regulators. The latter includes the mixed-lineage leukemia (MLL) family of histone methyltransferases that catalyze histone H3 lysine 4 di- and tri-methylation associated with gene activation. One such member, MLL1, is widely expressed in the central nervous system including the retina. However, its role in retinal development is unknown. To address this question, we knocked out Mll1 in mouse retinal progenitors, and discovered that MLL1 plays multiple roles in retinal development by regulating progenitor cell proliferation, cell type composition and neuron-glia balance, maintenance of horizontal neurons, and formation of functional synapses between neuronal layers required for visual signal transmission and processing. Altogether, our results suggest that MLL1 is indispensable for retinal neurogenesis and function development, providing a new paradigm for cell type-specific roles of known histone modifying enzymes during CNS tissue development.

The developing mouse retina is a tractable model for studying neurogenesis and differentiation. Although transgenic Cre mouse lines exist to mediate conditional genetic manipulations in developing mouse retinas, none of them act specifically in early developing rods. For conditional genetic manipulations of developing retinas, we created a Nrl-Cre mouse line in which the Nrl promoter drives expression of Cre in rod precursors. Our results show that Nrl-Cre expression is specific to the retina where it drives rod-specific recombination with a temporal pattern similar to endogenous Nrl expression during retinal development. This Nrl-Cre transgene does not negatively impact retinal structure and function. Taken together, our data suggest that the Nrl-Cre mouse line is a valuable tool to drive Cre-mediated recombination specifically in developing rods.

Key Clinical MessageThis case highlights an important lesson for laboratory genetic testing. Geneticists and Genetic Counselors should be aware that although rare, mosaic variegated aneuploidy should be considered if mosaic aneuploidies are observed on karyotype, particularly in the context of short stature.

Background/Aims: Temple syndrome is an imprinting disorder caused by maternal uniparental disomy of chromosome 14 (mat UPD14), paternal deletion of 14q32 or paternal hypomethylation of the intergenic differentially methylated region (MEG3/DLK1 IG-DMR). Patients with Temple syndrome have pre- and postnatal growth restriction, short stature, hypotonia, small hands and feet and precocious puberty. We sought to determine whether treatment with growth hormone improves growth outcomes in patients with Temple syndrome. Methods: This was a retrospective observational study reviewing the medical records of 14 patients with Temple syndrome, 7 of whom were treated with growth hormone. Results: After 1 year of growth hormone treatment, the height standard deviation score (SDS) increased a median of 1.31 SDS with a median increased height velocity of 5.30 cm/year. Conclusions: These results suggest short-term improvement in height SDS with growth hormone treatment similar to the response in patients treated under the small for gestational age indication. We recommend considering growth hormone therapy in all patients with Temple syndrome who have short stature.

We aim to assess if genotype–phenotype correlations are present within ocular manifestations of Kabuki syndrome (KS) among a large multicenter cohort. We conducted a retrospective, medical record review including clinical history and comprehensive ophthalmological examinations of a total of 47 individuals with molecularly confirmed KS and ocular manifestations at Boston Children's Hospital and Cincinnati Children's Hospital Medical Center. We assessed information regarding ocular structural, functional, and adnexal elements as well as pertinent associated phenotypic features associated with KS. For both type 1 KS (KS1) and type 2 KS (KS2), we observed more severe eye pathology in nonsense variants towards the C‐terminus of each gene, KMT2D and KDM6A, respectively. Furthermore, frameshift variants appeared to be not associated with structural ocular elements. Between both types of KS, ocular structural elements were more frequently identified in KS1 compared with KS2, which only involved the optic disc in our cohort. These results reinforce the need for a comprehensive ophthalmologic exam upon diagnosis of KS and regular follow‐up exams. The specific genotype may allow risk stratification of the severity of the ophthalmologic manifestation. However, additional studies involving larger cohorts are needed to replicate our observations and conduct powered analyses to more formally risk‐stratify based on genotype, highlighting the importance of multicenter collaborations in rare disease research.

Mosaic genetic mutations may be somatic, germline, or "gonosomal" and have the potential to cause genetic syndromes, disorders, or malformations. Mutations can occur at any point in embryonic development and the timing determines the extent of distribution of the mutation throughout the body and different tissue types. The eye and visual pathway offer a unique opportunity to study somatic and gonosomal mosaic mutations as the eye consists of tissues derived from all three germ layers allowing disease pathology to be assessed with noninvasive imaging. In this review, we describe systemic and ocular manifestations in a child with mosaic Coffin-Siris syndrome. The patient presented with a significant medical history of accommodative esotropia and hyperopia, macrocephaly, polydactyly, global developmental delay, hypotonia, ureteropelvic junction (UPJ) obstruction, and brain MRI abnormalities. The ophthalmic findings in this patient were nonspecific, however, they are consistent with ocular manifestations reported in other patients with Coffin-Siris syndrome. We also review ophthalmic findings of select mosaic chromosomal and single-gene disorders. Ophthalmic assessment alongside clinical genetic testing may play an important role in diagnosis of genetic syndromes as well as understanding disease pathology, particularly when mosaicism plays a role.

Exome sequencing (ES) became clinically available in 2011 and promised an agnostic, unbiased next-generation sequencing (NGS) platform for patients with symptoms believed to have a genetic etiology. The diagnostic yield of ES has been estimated to be between 25–40% and may be higher in specific clinical scenarios. Those who remain undiagnosed may have no molecular findings of interest on ES, variants of uncertain significance in genes that are linked to human disease, or variants of uncertain significance in candidate genes that are not definitively tied to human disease. Recent evidence suggests that a post-exome evaluation consisting of clinical re-phenotyping, functional studies of candidate variants in known genes, and variant reevaluation can lead to a diagnosis in 5–15% of additional cases. In this brief research study, we present our experience on post-exome evaluations in a cohort of patients who are believed to have a genetic etiology for their symptoms. We have reached a full or partial diagnosis in approximately 18% (6/33) of cases that have completed evaluations to date. We accomplished this by utilizing NGS-based methods that are available on a clinical basis. A sample of these cases highlights the utility of ES reanalysis with updated phenotyping allowing for the discovery of new genes, re-adjudication of known variants, incorporating updated phenotypic information, utilizing functional testing such as targeted RNA sequencing, and deploying other NGS-based testing methods such as gene panels and genome sequencing to reach a diagnosis.

Background: Familial hemophagocytic lymphohistiocytosis (FHL) is an immunological disorder characterized by overactivation of macrophages and T lymphocytes. This autosomal recessive condition has been characterized into multiple types depending on the genetic etiology. FHL type 3 is associated with bi-allelic pathogenic variants in the UNC13D gene. Case presentation: We present a 12-year diagnostic odyssey for a family with FHL that signifies the advances of FHL genetic testing in a diagnostic genetics laboratory with expertise in heritable immunodeficiencies. We describe the first case of a large UNC13D gross deletion in transto a sequence variant in a family with FHL3, which may have been mediated by Alu elements within introns 12 and 25 of the UNC13D gene. Conclusions: This case highlights the importance of reevaluating past genetic testing for a patient and family as test technology evolves in order to end a diagnostic odyssey.