NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.

PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Impact of integrated translational research on clinical exome sequencing.

PURPOSE: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. METHODS: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. RESULTS: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. CONCLUSION: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

Haploinsufficiency as a disease mechanism in GNB1-associated neurodevelopmental disorder.

BACKGROUND: GNB1 encodes a subunit of a heterotrimeric G-protein complex that transduces intracellular signaling cascades. Disruptions to the gene have previously been shown to be embryonic lethal in knockout mice and to cause complex neurodevelopmental disorders in humans. To date, the majority of variants associated with disease in humans have been missense variants in exons 5-7. METHODS: Genetic sequencing was performed on two patients presenting with complex neurological phenotypes including intellectual disability, hypotonia, and in one patient seizures. Reported variants were assessed using RNA sequencing and functional BRET/BiFC assays. RESULTS: A splice variant reported in patient 1 was confirmed to cause usage of a cryptic splice site leading to a truncated protein product. Patient 2 was reported to have a truncating variant. BRET and BiFC assays of both patient variants confirmed both were deficient in inducing GPCR-induced G protein activation due to lack of dimer formation with the Gγ subunit. CONCLUSION: Here, we report two patients with functionally confirmed loss of function variants in GNB1 and neurodevelopmental phenotypes including intellectual disability, hypotonia, and seizures in one patient. These results suggest haploinsufficiency of GNB1 is a mechanism for neurodevelopmental disorders in humans.

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome.

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.

Profound intellectual disability caused by homozygous TRAPPC9 pathogenic variant in a man from Malta.

BACKGROUND: Intellectual disability is a complex multi-faceted condition with diverse underlying etiologies. One rare form of intellectual disability is secondary to the loss of TRAPPC9, an activator of NF-κB and a mediator of intracellular protein processing and trafficking. TRAPPC9 deficiency has been described in 48 patients with more than 15 pathologic variants. METHOD: Clinical evaluation, magnetic resonance imaging, and whole-exome sequencing were used to characterize the underlying cause of absent speech, restricted/repetitive behaviors, and worsening behavioral outbursts in 27-year-old man from Malta. RESULTS: Magnetic Resonance Imaging showed morphologic abnormalities, including global cerebral and cerebellar hypoplasia. Genetic analysis through Whole Exome Sequencing identified a homozygous deletion (c.568_574del) in TRAPPC9 resulting in a frameshift, premature stop codon, and ultimately a truncated protein (p.Trp190Argfs*95). In this case, the pathogenic variant was homozygous, identified in both of the parents without known consanguinity. CONCLUSION: Given the phenotype and genotype consistent with a deficiency in TRAPPC9, it is likely that this patient represents a novel case of this rare genetic syndrome. Specifically, this case, in the context of 48 total reported patients, raises questions as to the geographic origin of the pathologic variant and optimal detection and therapeutic intervention for this condition.

Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures.

The Jumonji domain containing 1C (JMJD1C) gene encodes the Jumonji domain-containing protein 1C (JMJD1C) and is a member of the jmJC domain-containing protein family involved in histone demethylation that is expressed in the brain. We report seven, unrelated patients with developmental delays or intellectual disability and heterozygous, de novo sequence variants in JMJD1C. All patients had developmental delays, but there were no consistent additional findings. Two patients were reported to have seizures for which there was no other identified cause. De novo, deleterious sequence variants in JMJD1C have previously been reported in patients with autism spectrum disorder and a phenotype resembling classical Rett syndrome, but only one JMJD1C variant has undergone functional evaluation. In all of the seven patients in this report, there was a plausible, alternative explanation for the neurocognitive phenotype or a modifying factor, such as an additional potentially pathogenic variant, presence of the variant in a population database, heteroplasmy for a mitochondrial variant or mosaicism for the JMJD1C variant. Although the de novo variants in JMJD1C are likely to be relevant to the developmental phenotypes observed in these patients, we conclude that further data supporting the association of JMJD1C variants with intellectual disability is still needed.

Complex phenotypes in ALG12-congenital disorder of glycosylation (ALG12-CDG): Case series and review of the literature.

ALG12-congenital disorder of glycosylation (ALG12-CDG) is a rare disorder caused by a deficiency of dolichol-P-mannose:Man7GlcNAc2-PP-dolichyl-α-6-mannosyltransferase which presents with intellectual disability, hypotonia, dysmorphic features, low IgG levels with recurrent infections, male genital hypoplasia, and coagulation abnormalities. We report a unique family with three affected individuals, including two older brothers with only cognitive and coagulation defects and a younger brother who died from a severe multisystem disease at age 18 months. The two living brothers are the oldest and mildest cases of ALG12-CDG described thus far. Whole exome sequencing of the older brothers revealed a previously described c.1001delA (p.N334TfsX15) pathogenic variant and a c.671C > T (p.T224 M) variant of uncertain significance in ALG12. Our cases broaden the recognized genetic and phenotypic spectrum of this disorder and suggest a role for other genetic and environmental factors in modulating disease phenotype.

Perspectives on facilitating whole exome sequencing for international patients at Mayo Clinic.

Whole exome sequencing (WES) has become a fundamental component of genetic evaluation and diagnosing rare genetic diseases. This test is now offered to patients from a wide variety of cultural backgrounds and in various clinical and research settings. This commentary is a reflection of one group of clinical genetic counselors' experiences in facilitating WES for patients who come from outside the United States for genetic evaluation and pursue WES. This patient population in our clinic primarily consists of individuals from the Middle East and presents recurrent logistical and counseling challenges. We aim to describe our international patient population, illuminate the challenges we have faced and illustrate how we have addressed these challenges.

Descemet's membrane endothelial keratoplasty: clinical results of single versus triple procedures (combined with cataract surgery).

PURPOSE: To compare the outcomes of triple Descemet's membrane endothelial keratoplasty (DMEK) versus DMEK alone in pseudophakic eyes. DESIGN: Retrospective, comparative, interventional case series. PARTICIPANTS: Patients with Fuchs' endothelial dystrophy, secondary corneal edema, and prior failed endothelial keratoplasty with or without prior cataract extraction. METHODS: Outcomes of 492 DMEK procedures performed between April 2010 and August 2012 were reviewed; 292 pseudophakic eyes underwent DMEK (group 1) and 200 eyes had concurrent cataract surgery with DMEK (group 2). MAIN OUTCOME MEASURES: Corrected distance visual acuity, endothelial cell loss, immediate and early postoperative complications. RESULTS: The mean age at the time of surgery was 70 years (range, 47-94 years) in group 1 and 64 years (range, 46-90 years) in group 2 (P <0.0001). At 6 months, the median corrected distance visual acuity was 20/25 (range, 20/16-20/80; n = 164) in group 1 and 20/20 (range, 20/16-20/100; n = 121) in group 2 (P <0.0001), excluding 21 eyes with retinal or optic nerve problems. The DMEK graft failed to clear in 9 eyes (3.1%) in group 1 and 7 eyes (3.5%) in group 2 (P = 0.34); all were regrafted successfully with DMEK. No further graft failures occurred during the follow-up period. The air reinjection rate was 30% in group 1 and 29% in group 2 (P = 0.69). The air reinjection rate dropped significantly in both groups, from 45% to 16%, after use of viscoelastic was eliminated during the tissue insertion step. The median endothelial cell loss at 3 to 6 months did not differ significantly between groups (26% in both). CONCLUSIONS: Triple DMEK was not associated with any higher risk of complications than DMEK alone. Compared with sequential management of patients with concomitant cataract and endothelial dysfunction, triple DMEK is an effective strategy in rapid visual rehabilitation and offers the advantage of a 1-stage procedure, with reduced risks and costs.

Rapid sequential endothelial keratoplasty with and without combined cataract extraction.

PURPOSE: To evaluate the outcomes of bilateral Descemet membrane endothelial keratoplasty (DMEK) combined with cataract extraction as indicated within a 1- to 2-week timeframe for treatment of Fuchs endothelial corneal dystrophy. SETTING: Private practice, Indianapolis, Indiana, USA. DESIGN: Case series. METHODS: This retrospective review identified patients who had DMEK in both eyes within 2 weeks. RESULTS: The study comprised 12 patients (median age 61 years). Seven patients had bilateral DMEK 1 week apart and 5 patients, 2 weeks apart. Twelve eyes had triple procedures (cataract extraction, intraocular lens implantation, DMEK), 7 eyes were pseudophakic before DMEK, and 5 eyes had clear lenses and remained phakic after DMEK. Preoperatively, the median corrected distance visual acuity (CDVA) was 20/40 (range 20/15 to 20/70). By 1 month postoperatively, the median CDVA had improved to 20/25 (range 20/15 to 20/70). The median CDVA in the 10 patients examined between 3 months and 6 months postoperatively was 20/20 (range 20/15 to 20/30). All grafts successfully attached and cleared. Four patients had bilateral air reinjection and 1 patient had unilateral air reinjection to treat partial graft detachment. The rate of air reinjection was comparable between single and triple procedures (P=.65). No other complications were noted. CONCLUSIONS: Patients with bilateral visual impairment associated with Fuchs dystrophy can have both eyes treated with DMEK within 1 to 2 weeks. With DMEK, corneal transplantation begins to approach cataract surgery in the speed of visual recovery and the time to full resumption of daily activities.