Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-specific 2 (Gas2)-related (GAR) domain. Heterozygous MACF1 missense variants affecting the zinc-binding residues in this domain result in a distinctive cortical and brain stem malformation. Evidence for other MACF1-associated disorders is still limited. Here, we present a cohort of 45 individuals with heterozygous or bi-allelic MACF1 variants to explore the phenotypic spectrum and assess possible pathogenic relevance. We observe that de novo heterozygous missense variants in the EF-hand domains also result in distinctive brain malformation and provide experimental evidence that variants in the EF-hand/GAR module increase microtubule binding, suggestive of a toxic gain of function. Notably, no phenotype-genotype correlation was possible for the remaining heterozygous variants in other domains. A clinical review of eight families with bi-allelic variants reveals a possible complex neurodevelopmental syndrome of the central and peripheral nervous systems. In these individuals, bi-allelic variants mostly affect the Plakin domain. Furthermore, RNA sequencing and chromatin immunoprecipitation (ChIP) analyses of human fetal brain tissue reveal five MACF1 isoforms with region-specific expression, differing in their exon 1 transcription start sites but splicing to a common exon 2. This differential expression explains the frontal-predominant lissencephaly in an individual with a homozygous stop-gain in exon 1 (MACF1-204: c.70C>T [p.Arg24∗]), as this isoform is preferentially expressed in the frontal cortex. We conclude that MACF1-related disorders are strictly linked to domain function and the level of transcript expression, explaining the observed wide clinical heterogeneity.

Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function.

Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by the absence of a fully functional dystrophin protein in myocytes. In skeletal muscle, the lack of dystrophin ultimately results in muscle wasting and the replacement of myocytes with fatty or fibrous tissues. In the heart, cardiomyocytes eventually fail and cause fatal cardiomyopathy. We present a case of a male patient and his younger brother with a maternally inherited inverted insertion of approximately 306 kb of chromosome 10 in the deep intronic region between exons 44 and 45 of the DMD gene, leading to Duchenne muscular dystrophy. Chromosomal microarray, comprehensive muscular dystrophy genetic testing, and whole exome sequencing were negative. Targeted transcriptome RNA sequencing at an external lab showed no aberrant splicing. Research whole genome sequencing identified the copy number gain and insertion. Subsequent reanalysis of the RNA sequencing data showed possible aberrant splicing involving DMD exons 44-45, and research RNA sequencing revealed a fusion between the DMD gene on the minus strand of chromosome X and the PFKFB3 gene on the plus strand of chromosome 10. We demonstrate that whole genome sequencing can be valuable for identifying intronic events in the DMD gene previously undetected or not reported by traditional clinical testing.

Genetic defects affecting steroid biosynthesis cause cortisol deficiency and differences of sex development; among these defects are recessive mutations in the steroidogenic enzymes CYP11A1 and CYP11B, whose function is supported by reducing equivalents donated by ferredoxin reductase ( FDXR ) and ferredoxin. So far, mutations in the mitochondrial flavoprotein FDXR have been associated with a progressive neuropathic mitochondriopathy named FDXR-related mitochondriopathy (FRM), but cortisol insufficiency has not been documented. However, patients with FRM often experience worsening or demise following stress associated with infections. We investigated 2 female patients with FRM carrying the potentially novel homozygous FDXR mutation p.G437R with ambiguous genitalia at birth and sudden death in the first year of life; they presented with cortisol deficiency and androgen excess compatible with 11-hydroxylase deficiency. In addition, steroidogenic FDXR-variant cell lines reprogrammed from 3 patients with FRM fibroblasts displayed deficient mineralocorticoid and glucocorticoid production. Finally, Fdxr-mutant mice allelic to the severe p.R386W human variant showed reduced progesterone and corticosterone production. Therefore, our comprehensive studies show that human FDXR variants may cause compensated but possibly life-threatening adrenocortical insufficiency in stress by affecting adrenal glucocorticoid and mineralocorticoid synthesis through direct enzyme inhibition, most likely in combination with disturbed mitochondrial redox balance.

This commentary is on the original article by Chatur et al. on pages 1008–1016 of this issue.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Background In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31. Objective The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia. Methods Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function. Results Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility. Conclusion A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.

CONTEXT:Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome is a recently described, rare disorder characterized by anterior pituitary hormone deficiencies and common variable immunodeficiency associated with NFKB2 mutations. Posterior pituitary hormone deficiencies have not been reported in patients with DAVID syndrome.CASE DESCRIPTION:We report a pediatric patient who initially presented with hypogammaglobulinemia and alopecia totalis, who was identified to have a de novo NFKB2 mutation at one year of age. He developed central diabetes insipidus and central adrenal insufficiency at three and four years of age, respectively. At seven years of age, he had not developed GH or TSH deficiencies. Whole exome sequencing ruled out known genetic causes of central diabetes insipidus, adrenal insufficiency, and hypopituitarism.CONCLUSION:This is a report of central diabetes insipidus in a patient with DAVID syndrome caused by an NFKB2 mutation. This case report expands the evolving endocrine phenotype associated with NFKB2 mutations beyond anterior pituitary deficiencies.

Microarray testing has revolutionized clinical cytogenetics, as it provides a significantly higher resolution and greater clinical yield than karyotype analysis. This study assessed the clinical utility of single-nucleotide polymorphism microarray in patients with epilepsy. Study subjects were patients between the ages of birth to 23 years who were diagnosed with epilepsy and had a microarray performed at Cincinnati Children’s Hospital Medical Center. Statistical analysis explored the association of microarray results and brain magnetic resonance imaging (MRI), seizure type, and structural malformations. Approximately 17.7% (26/147) of participants had an abnormal microarray as defined by laboratory guidelines. There were no differences in frequency of abnormal brain MRI or seizure type between the abnormal and normal microarray groups. There was a higher prevalence of musculoskeletal malformations ( P < .0035) and cardiovascular malformations ( P < .0081) in subjects with abnormal microarrays. Clinicians should consider microarray analysis in individuals who have epilepsy, especially in combination with musculoskeletal malformation or cardiovascular malformation.

Partial trisomy 9q involving the duplication of band 9q22 is manifested by a constellation of symptoms including short stature, intellectual disability, microcephaly, pyloric stenosis, facial dysmorphism, and various defects of the heart, distal extremities, eyes, thyroid, and esophagus. In three family members with growth retardation, mild intellectual disability, and mild facial dysmorphism, array‐based comparative genomic hybridization analyses showed a familial microduplication at 9q22.3. On the basis of the described functions of the duplicated genes, PTCH1 represents a candidate gene that may be responsible for the phenotypic findings, although the 14 other genes in this duplicated segment may also contribute to the phenotype. The current report provides evidence to support a specific phenotype associated with a 9q22.3 microduplication and confirm localization of a subset of the trisomy 9q phenotype to this chromosomal region. © 2011 Wiley‐Liss, Inc.

Acute necrotizing encephalopathy (ANE) is a devastating and rapidly progressive neurologic disorder that occurs in healthy children after common viral infections. Typically, ANE is sporadic and does not recur. However, familial (ANE1) and recurrent cases have been reported and were recently linked to mutations in RANBP2 (RAN-binding protein 2). We report here a multiply affected kindred with recurrent familial ANE. These affected male siblings (a set of twins and their older brother) all presented with prodromal fever and upper respiratory tract infection that progressed within 72 hours to seizures, coma, and ultimately death, a course that is typical of ANE. It should be noted that 1 brother was treated with early aggressive management, including corticosteroids, and he survived for an additional 5 years. This represents the second reported case of familial ANE in the United States and the only case of male siblings with consanguineous parents. We hope that early recognition and growing awareness can lead to more effective treatment and better outcomes in the future.

Acute necrotizing encephalopathy (ANE) typically affects young, healthy children who develop rapid‐onset severe encephalopathy triggered by viral infections. This disease is more commonly reported in Japan but occurs worldwide, although it remains under‐recognized in Western countries. An autosomal dominant form, ANE1, was recently identified. We report the details of a 9‐year‐old Caucasian female who experienced recurrent ANE episodes at the ages of 9 months and 9 years. Brain magnetic resonance imaging findings were characteristic of ANE during both episodes, although more extensive in the recent episode, which resulted in severe neurological sequelae; influenza A was identified on bronchoalveolar lavage during this episode. Interestingly, there was evidence of peripheral polyneuropathy during the recent episode, which has not previously been described in sporadic ANE. Both the patient and her mother, who had also had postviral polyneuritis in the past, harbour a mutation in Ran‐binding protein 2 (RANBP2); this occurred de novo in the mother and confers genetic susceptibility to ANE. Our case suggests that recurrent disease and/or an expanded clinical phenotype raises the possibility of ANE1; positive family history, although supportive, is not necessary as the mutation can occur de novo. Increased awareness may lead to earlier recognition and better treatment options.

American Journal of Medical Genetics Part AVolume 152A, Issue 8 p. 2115-2119 Research Letter Late manifestations of tricho-rhino-pharangeal syndrome in a patient: Expanded skeletal phenotype in adulthood† Kosuke Izumi, Kosuke Izumi Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio Department of Genetics, Case Western Reserve University, Cleveland, Ohio Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OhioSearch for more papers by this authorMasaki Takagi, Masaki Takagi Department of Pediatrics, Keio University School of Medicine, Tokyo, JapanSearch for more papers by this authorAditi S. Parikh, Aditi S. Parikh Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio Department of Genetics, Case Western Reserve University, Cleveland, Ohio Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OhioSearch for more papers by this authorAmanda Hahn, Amanda Hahn Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio Department of Genetics, Case Western Reserve University, Cleveland, OhioSearch for more papers by this authorShana N. Miskovsky, Shana N. Miskovsky Department of Orthopaedic Surgery, University Hospitals Case Medical Center, Cleveland, OhioSearch for more papers by this authorGen Nishimura, Gen Nishimura Department of Radiology, Tokyo Metoropolitan Kiyose Children's Hospital, Tokyo, JapanSearch for more papers by this authorChiharu Torii, Chiharu Torii Department of Pediatrics, Keio University School of Medicine, Tokyo, JapanSearch for more papers by this authorKenjiro Kosaki, Kenjiro Kosaki Department of Pediatrics, Keio University School of Medicine, Tokyo, JapanSearch for more papers by this authorTomonobu Hasegawa M.D., Corresponding Author Tomonobu Hasegawa M.D. [email protected] Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan Tomonobu Hasegawa, Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Derek E. Neilson, Division of Human Genetics, Cincinnati Children's Medical Center, Cincinnati, OH 45229.Search for more papers by this authorDerek E. Neilson M.D., Corresponding Author Derek E. Neilson M.D. [email protected] Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio Department of Genetics, Case Western Reserve University, Cleveland, Ohio Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio Tomonobu Hasegawa, Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Derek E. Neilson, Division of Human Genetics, Cincinnati Children's Medical Center, Cincinnati, OH 45229.Search for more papers by this author Kosuke Izumi, Kosuke Izumi Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio Department of Genetics, Case Western Reserve University, Cleveland, Ohio Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OhioSearch for more papers by this authorMasaki Takagi, Masaki Takagi Department of Pediatrics, Keio University School of Medicine, Tokyo, JapanSearch for more papers by this authorAditi S. Parikh, Aditi S. Parikh Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio Department of Genetics, Case Western Reserve University, Cleveland, Ohio Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OhioSearch for more papers by this authorAmanda Hahn, Amanda Hahn Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio Department of Genetics, Case Western Reserve University, Cleveland, OhioSearch for more papers by this authorShana N. Miskovsky, Shana N. Miskovsky Department of Orthopaedic Surgery, University Hospitals Case Medical Center, Cleveland, OhioSearch for more papers by this authorGen Nishimura, Gen Nishimura Department of Radiology, Tokyo Metoropolitan Kiyose Children's Hospital, Tokyo, JapanSearch for more papers by this authorChiharu Torii, Chiharu Torii Department of Pediatrics, Keio University School of Medicine, Tokyo, JapanSearch for more papers by this authorKenjiro Kosaki, Kenjiro Kosaki Department of Pediatrics, Keio University School of Medicine, Tokyo, JapanSearch for more papers by this authorTomonobu Hasegawa M.D., Corresponding Author Tomonobu Hasegawa M.D. [email protected] Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan Tomonobu Hasegawa, Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Derek E. Neilson, Division of Human Genetics, Cincinnati Children's Medical Center, Cincinnati, OH 45229.Search for more papers by this authorDerek E. Neilson M.D., Corresponding Author Derek E. Neilson M.D. [email protected] Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio Department of Genetics, Case Western Reserve University, Cleveland, Ohio Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio Tomonobu Hasegawa, Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Derek E. Neilson, Division of Human Genetics, Cincinnati Children's Medical Center, Cincinnati, OH 45229.Search for more papers by this author First published: 20 July 2010 https://doi.org/10.1002/ajmg.a.33511Citations: 11 † How to Cite this Article: Izumi K, Takagi M, Parikh AS, Hahn A, Miskovsky SN, Nishimura G, Torii C, Kosaki K, Hasegawa T, Neilson DE. 2010. Late manifestations of tricho-rhino-pharangeal syndrome in a patient: Expanded skeletal phenotype in adulthood. Am J Med Genet Part A 152A:2120–2122. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL REFERENCES Collins FS, Brooks LD, Chakravarti A. 1998. A DNA polymorphism discovery resource for research on human genetic variation. Genome Res 8: 1229– 1231. Cope R, Beals RK, Bennett RM. 1986. The trichorhinophalangeal dysplasia syndrome: Report of eight kindreds, with emphasis on hip complications, late presentations, and premature osteoarthrosis. 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Purpose of review Acute necrotizing encephalopathy (ANE) presents with fulminant encephalopathy and characteristic brain lesions following viral infection. The rarity and unpredictability of the disorder have significantly impaired its study. Growing recognition of ANE and the discovery of causative missense mutations in the nuclear pore gene RANBP2 give promising steps toward unraveling this disease. This review summarizes recent advances of clinical and scientific understanding of ANE. Recent findings Inflammatory factors participate in the pathogenesis of ANE, but the lack of difference between influenza and noninfluenza ANE focuses attention on the abnormal host response as causative. Early treatment with steroids provides the best outcome for patients who do not have brainstem lesions. Missense mutations in RANBP2 cause the majority of familial and recurrent ANE cases, but other single-gene causes of ANE are possible for familial, recurrent, and sporadic cases. Summary Early recognition and systematic evaluation of ANE are necessary. Modeling ANE as a genetic disorder may provide the most immediate gains in the understanding and treatment of ANE and related disorders.

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.

We describe eight members from two large Amish kindreds who share a phenotype characterized by early-onset pigmentary retinopathy and myopia, global developmental delay and mental retardation, microcephaly, short stature, hypotonia, joint hyperextensibility, small hands and feet, common facial appearance, and friendly disposition. Several of the children had intermittent granulocytopenia. The phenotypic occurrence in three siblings coupled with the increased coefficient of inbreeding in the Amish suggested that this disorder is autosomal recessive and due to a single founder allele. Despite similarity to the clinical features of Cohen syndrome, experienced dysmorphologists attending the 23rd David W. Smith Workshop suggested the facial gestalt of the Amish children was inconsistent with this diagnosis. We mapped the locus responsible for these individuals' phenotype to chromosome 8q22-q23, which contains the recently discovered Cohen syndrome gene, COH1. Complete sequencing of the COH1 gene identified a likely disease-causing frameshift mutation and a missense mutation in the Amish patients. A comparison of features among different Cohen syndrome populations with shared linkage to the COH1 locus or known COH1 gene mutations may allow for the determination of improved clinical criteria on which to suspect the diagnosis of Cohen syndrome. We conclude that facial gestalt seems to be an unreliable indicator of Cohen syndrome between ethnic populations, although it is quite consistent among affected individuals within a particular ethnic group. Other features common to almost all individuals with proven COH1 mutations, such as retinal dystrophy, myopia, microcephaly, mental retardation, global developmental delay, hypotonia, and joint hyperextensibility appear to be better clinical indicators of this disorder.