Heterozygous Mutations in SMARCA2 Reprogram the Enhancer Landscape by Global Retargeting of SMARCA4.

Mammalian SWI/SNF complexes are multi-subunit chromatin remodeling complexes associated with an ATPase (either SMARCA4 or SMARCA2). Heterozygous mutations in the SMARCA2 ATPase cause Nicolaides-Baraitser syndrome (NCBRS), an intellectual disability syndrome associated with delayed speech onset. We engineered human embryonic stem cells (hESCs) to carry NCBRS-associated heterozygous SMARCA2 K755R or R1159Q mutations. While SMARCA2 mutant hESCs were phenotypically normal, differentiation to neural progenitors cells (NPCs) was severely impaired. We find that SMARCA2 mutations cause enhancer reorganization with loss of SOX3-dependent neural enhancers and prominent emergence of astrocyte-specific de novo enhancers. Changes in chromatin accessibility at enhancers were associated with an increase in SMARCA2 binding and retargeting of SMARCA4. We show that the AP-1 family member FRA2 is aberrantly overexpressed in SMARCA2 mutant NPCs, where it functions as a pioneer factor at de novo enhancers. Together, our results demonstrate that SMARCA2 mutations cause impaired differentiation through enhancer reprogramming via inappropriate targeting of SMARCA4.

A dominant-negative SOX18 mutant disrupts multiple regulatory layers essential to transcription factor activity.

Few genetically dominant mutations involved in human disease have been fully explained at the molecular level. In cases where the mutant gene encodes a transcription factor, the dominant-negative mode of action of the mutant protein is particularly poorly understood. Here, we studied the genome-wide mechanism underlying a dominant-negative form of the SOX18 transcription factor (SOX18RaOp) responsible for both the classical mouse mutant Ragged Opossum and the human genetic disorder Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome. Combining three single-molecule imaging assays in living cells together with genomics and proteomics analysis, we found that SOX18RaOp disrupts the system through an accumulation of molecular interferences which impair several functional properties of the wild-type SOX18 protein, including its target gene selection process. The dominant-negative effect is further amplified by poisoning the interactome of its wild-type counterpart, which perturbs regulatory nodes such as SOX7 and MEF2C. Our findings explain in unprecedented detail the multi-layered process that underpins the molecular aetiology of dominant-negative transcription factor function.

Diacylglycerol Kinase ζ Regulates Macrophage Responses in Juvenile Arthritis and Cytokine Storm Syndrome Mouse Models.

Dysregulation of monocyte and macrophage responses are often observed in children with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS), a potentially fatal complication of chronic rheumatic diseases. Both conditions are associated with activation of TLR signaling in monocyte and macrophage lineage cells, leading to overwhelming inflammatory responses. Despite the importance of TLR engagement in activating proinflammatory macrophages, relatively little is known about activation of intrinsic negative regulatory pathways to attenuate excessive inflammatory responses. In this study, we demonstrate that loss of diacylglycerol (DAG) kinase (Dgk) ζ, an enzyme which converts DAG into phosphatidic acid, limits inflammatory cytokine production in an arthritic mouse model dependent on TLR2 signaling and in a CSS mouse model dependent on TLR9 signaling. In vitro, Dgkζ deficiency results in reduced production of TNF-α, IL-6, and IL-1ß and in limited M1 macrophage polarization. Mechanistically, Dgkζ deficiency decreases STAT1 and STAT3 phosphorylation. Moreover, Dgkζ levels are increased in macrophages derived from mice with CSS or exposed to plasma from sJIA patients with active disease. Our data suggest that Dgkζ induction in arthritic conditions perpetuates systemic inflammatory responses mediated by macrophages and highlight a potential role of Dgkζ-DAG/phosphatidic acid axis as a modulator of inflammatory cytokine production in sJIA and CSS.

Correlating Adaptive Optics Images to Clinical Findings in Juvenile Macular Dystrophy with Hypotrichosis in Siblings with Homozygous CDH3 Pathogenic Variation.

OBJECTIVE: We report on two German siblings diagnosed with congenital hypotrichosis and juvenile macular dystrophy, an extremely rare syndrome affecting both hair growth and visual functions. METHODS: A detailed ophthalmological examination was carried out including fundus examination, visual acuity assessment, visual field determination, color vision testing, and electrophysiology (electroretinography [ERG]). Additionally, fundus photography and autofluorescence imaging (FAF) was performed, along with optical coherence tomography (OCT) and adaptive optics (AO) fundus imaging. Targeted Sanger sequencing and next-generation gene panel sequencing were carried out. RESULTS: Macular dystrophy was evident in the fundus of both patients, as was a central scotoma in the static visual field. The kinetic visual field was normal. The ERG recordings were also normal, but the amplitudes of the multifocal ERG were reduced in the central 4-5° of the retina. The FAF images revealed a large central hypofluorescent area surrounded by a hyperfluorescent ring. The OCT images showed atrophy in the outer layers and tubulations. The AO images depicted a loss of central photoreceptors, as well as severe central atrophy in patient 1. A cone mosaic was observable in the peripheral AO fundus images of both patients. The disrupted cone mosaic on the AO images correlated with the hypofluorescent areas on autofluorescence. DNA testing identified the homozygous, likely pathogenic variant c.1508G>A/p.(Arg503His) (chr16:68719191) in the CDH3 gene. CONCLUSIONS: The two siblings revealed hypotrichosis and macular dystrophy in both eyes. The identification of a homozygous CDH3 mutation in each patient confirms the syndromic entity of hypotrichosis with juvenile macular degeneration.

Advances in computer-assisted syndrome recognition by the example of inborn errors of metabolism.

Significant improvements in automated image analysis have been achieved in recent years and tools are now increasingly being used in computer-assisted syndromology. However, the ability to recognize a syndromic facial gestalt might depend on the syndrome and may also be confounded by severity of phenotype, size of available training sets, ethnicity, age, and sex. Therefore, benchmarking and comparing the performance of deep-learned classification processes is inherently difficult. For a systematic analysis of these influencing factors we chose the lysosomal storage diseases mucolipidosis as well as mucopolysaccharidosis type I and II that are known for their wide and overlapping phenotypic spectra. For a dysmorphic comparison we used Smith-Lemli-Opitz syndrome as another inborn error of metabolism and Nicolaides-Baraitser syndrome as another disorder that is also characterized by coarse facies. A classifier that was trained on these five cohorts, comprising 289 patients in total, achieved a mean accuracy of 62%. We also developed a simulation framework to analyze the effect of potential confounders, such as cohort size, age, sex, or ethnic background on the distinguishability of phenotypes. We found that the true positive rate increases for all analyzed disorders for growing cohorts (n = [10...40]) while ethnicity and sex have no significant influence. The dynamics of the accuracies strongly suggest that the maximum distinguishability is a phenotype-specific value, which has not been reached yet for any of the studied disorders. This should also be a motivation to further intensify data sharing efforts, as computer-assisted syndrome classification can still be improved by enlarging the available training sets.

Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome.

Keratoderma-hypotrichosis-leukonychia totalis syndrome (KHLS) is an extremely rare, autosomal-dominant disorder characterized by severe skin hyperkeratosis, congenital alopecia and leukonychia totalis. The genetic defect underlying KHLS remained undetermined. By performing whole-exome sequencing in a family with KHLS, we identified a heterozygous mutation (c.23G>T [p.Gly8Val]) in GJA1, which cosegregated with the phenotype in the family. In an additional affected individual, we also found the identical de novo mutation which was absent in his unaffected family members. GJA1 encodes a gap junction protein connexin 43 (Cx43) which is ubiquitously expressed in various organs, including the epidermis and hair follicles. In vitro studies on HEK293 cells expressing Cx43(Gly8Val) found that the protein formed gap junction plaques between adjacent transfected cells, as observed in the wild-type. Dye-transfer experiments by microinjection of Lucifer yellow displayed functional gap junction of the Cx43(Gly8Val) mutant. Using patch clamp and Ca(2+) imaging methods, we observed that the Cx43(Gly8Val) hemichannel had significantly more openings than Cx43(WT), facilitating Ca(2+) influx at resting potential. Such gain-of-function effect might result in cytoplasmic Ca(2+) overload, accelerated apoptosis of keratinocytes and subsequent skin hyperkeratosis. Taken together, our results demonstrated that, with probably enhanced hemichannel activities, a mutation in GJA1 is linked to KHLS without extracutaneous involvement.

APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.

Hereditary hypotrichosis simplex is a rare autosomal dominant form of hair loss characterized by hair follicle miniaturization. Using genetic linkage analysis, we mapped a new locus for the disease to chromosome 18p11.22, and identified a mutation (Leu9Arg) in the adenomatosis polyposis down-regulated 1 (APCDD1) gene in three families. We show that APCDD1 is a membrane-bound glycoprotein that is abundantly expressed in human hair follicles, and can interact in vitro with WNT3A and LRP5-two essential components of Wnt signalling. Functional studies show that APCDD1 inhibits Wnt signalling in a cell-autonomous manner and functions upstream of beta-catenin. Moreover, APCDD1 represses activation of Wnt reporters and target genes, and inhibits the biological effects of Wnt signalling during both the generation of neurons from progenitors in the developing chick nervous system, and axis specification in Xenopus laevis embryos. The mutation Leu9Arg is located in the signal peptide of APCDD1, and perturbs its translational processing from the endoplasmic reticulum to the plasma membrane. APCDD1(L9R) probably functions in a dominant-negative manner to inhibit the stability and membrane localization of the wild-type protein. These findings describe a novel inhibitor of the Wnt signalling pathway with an essential role in human hair growth. As APCDD1 is expressed in a broad repertoire of cell types, our findings indicate that APCDD1 may regulate a diversity of biological processes controlled by Wnt signalling.

Hormones and clocks: do they disrupt the locks? Fluctuating estrogen levels during menopausal transition may influence clock genes and trigger chronic telogen effluvium.

Chronic telogen effluvium describes the clinical condition noted mostly in middle-aged women of increased, diffuse scalp hair shedding that is prolonged and often presents with a fluctuating course that may continue for years but does not lead to visible hair thinning. Despite its description almost 20 years ago, the underlying pathologic cause of CTE is yet to be identified. However the culmination of research in the field of hair biology and the burgeoning field of chronobiology may lead to exciting breakthroughs in our understanding of CTE. In this paper the current literature on CTE is reviewed and a hypothesis is put forth that CTE may be triggered by hormonal fluctuations and alterations in circadian control genes.

Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin.

We have identified nonsense mutations in the gene CDSN (encoding corneodesmosin) in three families suffering from hypotrichosis simplex of the scalp (HSS; OMIM 146520). CDSN, a glycoprotein expressed in the epidermis and inner root sheath (IRS) of hair follicles, is a keratinocyte adhesion molecule. Truncated CDSN aggregates were detected in the superficial dermis and at the periphery of hair follicles. Our findings suggest that CDSN is important in normal scalp hair physiology.

Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis.

Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant hair disorder. Through the study of a mouse model, we identified a mutation in the 5'-untranslated region of the hairless (HR) gene in patients with MUHH in a Caucasian family. The corresponding mutation, named 'hairpoor', was found in mutant mice that were generated through N-ethyl-N-nitrosourea mutagenesis. Hairpoor mouse mutants display partial hair loss at an early age and progress to near alopecia, which resembles the MUHH phenotype. This mutation conferred overexpression of HR through translational derepression and, in turn, decreased the expression of Sfrp2, an inhibitor of the Wnt signaling pathway. This study indicates that the gain in function of HR also results in alopecia, as seen with the loss of function of HR, via abnormal upregulation of the Wnt signaling pathway.

The stem cell quiescence and niche signaling is disturbed in the hair follicle of the hairpoor mouse, an MUHH model mouse.

BACKGROUND: Hair follicle stem cells (HFSC) play an essential role in the maintenance of hair homeostasis; during the hair cycle, HFSC remain quiescent for most of its duration. The hairpoor mouse (+ /HrHp), an animal model of Marie-Unna hypotrichosis (MUHH), overexpresses hairless in the bulge, inner root sheath, and outer root sheath of HF and shows the same phenotype as in MUHH patients manifesting sparse hair with progression to alopecia with age. The aim of this study was to gain an understanding of the hair cycle and the status of HFSC during the hair cycle of the hairpoor mouse in order to delineate the pathogenesis of MUHH. METHODS: H&E staining was performed in order to define the state of the hair follicle. FACS analysis and immunostaining were performed at the 1st and 2nd telogen stages for observation of the HFSC. A label retaining assay was performed to determine the quiescent state of hair follicles. qRT-PCR was performed to determine expression of factors involved in niche signaling and Wnt signaling. RESULTS: We observed a drastic decrease in the number of hair follicles after the 1st telogen, followed by an intensified disturbance in the hair cycle with shorter anagen as well as 2nd telogen in the hairpoor mouse. A dramatic reduction in the number of CD34 expressing bulges as well as cells was observed at the telogen of the HFs, with prominent high proliferation of bulge cells, suggesting the loss of HFSC quiescence in the hairpoor mouse. The increased cell proliferation in HF was reiterated following the synchronization of the hair cycle, leading to acceleration of HF cycling. Reduced expression of Fgf18 and Bmp6, the factors involved in HFSC quiescence, was observed in the HFSC niche of the hairpoor mouse. In addition, disturbed expression of Wnt signaling molecules including Wnt7b, Wnt10b, and Sfrp1 was observed, which induced the telogen-to-anagen transition of HFs in the hairpoor mouse. CONCLUSIONS: These results indicate that the quiescent state of HFSC is not properly maintained in the hairpoor mouse, consequently leading HFs to the completely disarrayed hair cycle. These findings may provide an understanding of an underlying mechanism for development of alopecia with age in MUHH patients.

Vascular defects in a mouse model of hypotrichosis-lymphedema-telangiectasia syndrome indicate a role for SOX18 in blood vessel maturation.

Mutations in the transcription factor gene SOX18 cause vascular, lymphatic and hair follicle defects in humans with dominant and recessive forms of hypotrichosis-lymphedema-telangiectasia (HLT) syndrome. Here, we clarify the role of SOX18 in the vascular dysfunction in HLT by ultrastructural, immunofluorescence, molecular and functional analysis of vascular anomalies in embryos of the naturally occurring Sox18-mutant mouse strain ragged-opossum (Ra(Op)). Early genesis and patterning of vasculature was unimpaired in Ra(Op) embryos, but surface capillaries became enlarged from 12.5 dpc and embryos developed massive surface hemorrhage by 14.5 dpc. Large focal breaches in the endothelial barrier were observed, in addition to endothelial hyperplasia associated with impaired pericyte recruitment to the microvasculature. Expression of the genes encoding the endothelial factors MMP7, IL7R and N-cadherin was reduced in Ra(Op) embryos, suggesting that these are downstream targets of SOX18. Together, our results indicate that vascular anomalies in HLT arise from defects in regulation of genes required for the acquisition of structural integrity during microvascular maturation.

A new amyloidosis caused by fibrillar aggregates of mutated corneodesmosin.

Heterozygous nonsense mutations in the CDSN gene encoding corneodesmosin (CDSN), an adhesive protein expressed in cornified epithelia and hair follicles, cause hypotrichosis simplex of the scalp (HSS), a nonsyndromic form of alopecia. Truncated mutants of CDSN ((mut)CDSN), which bear the N-terminal adhesive Gly/Ser-rich domain (GS domain) of the protein, abnormally accumulate as amorphous deposits at the periphery of hair follicles and in the papillary dermis of the patient skin. Here, we present evidence that the (mut)CDSN deposits display an affinity for amyloidophilic dyes, namely Congo red and thioflavin T. We also detected the serum amyloid protein component in the dermis of HSS patients. We demonstrated that recombinant forms of (mut)CDSN and of the GS domain assemble in vitro into ring-shaped oligomeric structures and fibrils. The amyloid-like nature of the fibrils was demonstrated by dye binding and Fourier transform infrared spectrometry measurements. We showed that the ring-shaped oligomers of (mut)CDSN, but not the fibrillar forms, are toxic to cultured keratinocytes. Finally, online algorithms predicted the GS domain to be a particularly disordered region of CDSN in agreement with circular dichroism measurements. This identifies HSS as a human amyloidosis related to the aggregation of natively unfolded (mut)CDSN polypeptides into amyloid fibrils.

A KRT71 Loss-of-Function Variant Results in Inner Root Sheath Dysplasia and Recessive Congenital Hypotrichosis of Hereford Cattle.

Genodermatoses, such as heritable skin disorders, mostly represent Mendelian conditions. Congenital hypotrichosis (HY) characterize a condition of being born with less hair than normal. The purpose of this study was to characterize the clinicopathological phenotype of a breed-specific non-syndromic form of HY in Hereford cattle and to identify the causative genetic variant for this recessive disorder. Affected calves showed a very short, fine, wooly, kinky and curly coat over all parts of the body, with a major expression in the ears, the inner part of the limbs, and in the thoracic-abdominal region. Histopathology showed a severely altered morphology of the inner root sheath (IRS) of the hair follicle with abnormal Huxley and Henle's layers and severely dysplastic hair shafts. A genome-wide association study revealed an association signal on chromosome 5. Homozygosity mapping in a subset of cases refined the HY locus to a 690 kb critical interval encompassing a cluster of type II keratin encoding genes. Protein-coding exons of six positional candidate genes with known hair or hair follicle function were re-sequenced. This revealed a protein-changing variant in the KRT71 gene that encodes a type II keratin specifically expressed in the IRS of the hair follicle (c.281delTGTGCCCA; p.Met94AsnfsX14). Besides obvious phenocopies, a perfect concordance between the presence of this most likely pathogenic loss-of-function variant located in the head domain of KRT71 and the HY phenotype was found. This recessive KRT71-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002114-9913).

ARP-T1-associated Bazex-Dupré-Christol syndrome is an inherited basal cell cancer with ciliary defects characteristic of ciliopathies.

Actin-Related Protein-Testis1 (ARP-T1)/ACTRT1 gene mutations cause the Bazex-Dupré-Christol Syndrome (BDCS) characterized by follicular atrophoderma, hypotrichosis, and basal cell cancer. Here, we report an ARP-T1 interactome (PXD016557) that includes proteins involved in ciliogenesis, endosomal recycling, and septin ring formation. In agreement, ARP-T1 localizes to the midbody during cytokinesis and the basal body of primary cilia in interphase. Tissue samples from ARP-T1-associated BDCS patients have reduced ciliary length. The severity of the shortened cilia significantly correlates with the ARP-T1 levels, which was further validated by ACTRT1 knockdown in culture cells. Thus, we propose that ARP-T1 participates in the regulation of cilia length and that ARP-T1-associated BDCS is a case of skin cancer with ciliopathy characteristics.

Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA-PLA1alpha in autosomal recessive hypotrichosis.

Autosomal recessive hypotrichosis (ARH) is characterized by sparse hair on the scalp without other abnormalities. Three genes, DSG4, LIPH, and LPAR6 (P2RY5), have been reported to underlie ARH. We performed a mutation search for the three candidate genes in five independent Japanese ARH families and identified two LIPH mutations: c.736T>A (p.Cys246Ser) in all five families, and c.742C>A (p.His248Asn) in four of the five families. Out of 200 unrelated control alleles, we detected c.736T>A in three alleles and c.742C>A in one allele. Haplotype analysis revealed each of the two mutant alleles is derived from a respective founder. These results suggest the LIPH mutations are prevalent founder mutations for ARH in the Japanese population. LIPH encodes PA-PLA(1)alpha (LIPH), a membrane-associated phosphatidic acid-preferring phospholipase A(1)alpha. Two residues, altered by these mutations, are conserved among PA-PLA(1)alpha of diverse species. Cys(246) forms intramolecular disulfide bonds on the lid domain, a crucial structure for substrate recognition, and His(248) is one amino acid of the catalytic triad. Both p.Cys246Ser- and p.His248Asn-PA-PLA(1)alpha mutants showed complete abolition of hydrolytic activity and had no P2Y5 activation ability. These results suggest defective activation of P2Y5 due to reduced 2-acyl lysophosphatidic acid production by the mutant PA-PLA(1)alpha is involved in the pathogenesis of ARH.

A novel mutation in Hr causes abnormal hair follicle morphogenesis in hairpoor mouse, an animal model for Marie Unna Hereditary Hypotrichosis.

Hairpoor mice (Hr(Hp)) were derived through N-ethyl-N-nitrosourea (ENU) mutagenesis. These mice display sparse and short hair in the Hr(Hp)/+ heterozygous state and complete baldness in the Hr(Hp)/Hr(Hp) homozygous state. This phenotype was irreversible and was inherited in an autosomal semidominant manner. Hair follicles (HFs) of Hr(Hp)/+ mice underwent normal cycling and appeared normal, although smaller than those of the wild-type mice. In contrast, HFs of Hr(Hp)/Hr(Hp) mice became cyst-like structures by postnatal day (P) 21. The number and length of vibrissae decreased in a dose-dependent manner as the number of mutant alleles increased. A positional candidate gene approach was used to identify the gene responsible for the hairpoor phenotype. Genetic linkage analysis determined that the hairpoor locus is 2 cm from D14Mit34 on chromosome 14. Sequence analysis of the exons of the candidate gene hairless revealed a T-to-A transversion mutation at nucleotide position 403 (exon 2), presumably resulting in abolishment of an upstream open reading frame (uORF). In addition, we also found that the near-naked mouse (Hr(N)), a spontaneously arising mutant, harbors a A402G transition in its genome. Both mutations were in the uATG codon of the second uORF in the 5' UTR and corresponded to the mutations identified in Marie Unna Hereditary Hypotrichosis (MUHH) patients. In the present study we describe the phenotype, histological morphology, and molecular etiology of an animal model of MUHH, the hairpoor mouse.

Proteomic manifestations of genetic defects in autosomal recessive congenital ichthyosis.

Numerous genetic conditions give rise to a scaly skin phenotype as a result of impaired barrier function. Present work investigates the degree to which the departure from normal of ichthyosis corneocytes on the skin surface depends upon the basic defect as judged by proteomic profiling. Analyzing autosomal recessive congenital ichthyosis arising from defects in the genes PNPLA1, SDR9C7 and TGM1 revealed that profiles of PNPLA1 samples displayed the greatest degree of departure from normal control epidermis, with SDR9C7 samples nearly as divergent, and TGM1 the least divergent. Although the profiles were distinctive, each displaying a set of altered protein levels, they exhibited alterations in 20 proteins in common, of which 15 were expressed consistently at higher and 5 at lower levels. Departure from the normal profile was examined at three different anatomic sites (forearm, forehead, leg). Reflecting that the normal protein profile differed at these sites, comparing profiles from afflicted subjects revealed that the degree of alteration in profile was site-dependent. These results suggest proteomic profiling can provide a quantitative measure of departure from the normal state of epidermis. Further development may help characterize consequences of the genetic defects, including perturbation of signaling pathways, and supplement visual evaluation of treatment. SIGNIFICANCE: ARCI are rare cornification disorders caused by mutations in at least 14 different genes leading to perturbed metabolism and organization of constituent biomolecules of cornified envelopes. The phenotypic manifestations of the disorder vary among individuals with the same as well as different genetic defects and even at different anatomic sites within the same individual. The present study investigates the proteomic disturbances at three anatomic sites in patients carrying mutations in three different genes. Our findings provide a basis for elucidating genotype to proteome relationships for ARCI, further investigation of which may help to delineate the underlying pathways as well as to identify new drug targets.

Aortic Dilatation Associated With a De Novo Mutation in the SOX18 Gene: Expanding the Clinical Spectrum of Hypotrichosis-Lymphedema-Telangiectasia Syndrome.

BACKGROUND: We report a 13-year-old female patient followed since birth for multiple rare congenital defects, including hypotrichosis, telangiectasia, and severe dilatation of the ascending aorta. METHODS: Comprehensive phenotype assessment throughout childhood included repeated echocardiographic measurements, evaluation of renal function, and immunohistochemical analysis of skin biopsy samples. Whole-exome sequencing was performed for the patient and both unaffected parents. RESULTS: We identified a novel de novo mutation in the transcription factor SOX18 (c.481C>T:p.Gln161*) in the patient, which was absent in all unaffected family members. Echocardiography revealed early onset and progressive dilatation of the ascending aorta. Skin biopsy results confirmed the defects of the blood vasculature in the presence of intact lymphatic vessels. Assessment of renal function did not show any signs of renal problems or renal failure in the patient. CONCLUSIONS: The genetic finding of a pathogenic SOX18 mutation enabled the diagnosis of the rare hypotrichosis-lymphedema-telangiectasia syndrome in our patient. The identification of a novel stop gain mutation in the SOX18 gene in association with dilatation of the aorta highlights the importance of this gene during the development of the circulatory system. Our study highlights the importance of whole-exome sequencing in the rapid identification of genes and gene mutations involved in rare conditions and thus expanding the knowledge and spectrum of clinical manifestations associated with them.

Characterization of CDH3-Related Congenital Hypotrichosis With Juvenile Macular Dystrophy.

IMPORTANCE: Congenital hypotrichosis with juvenile macular dystrophy (HJMD) is a rare disorder presenting in childhood and adolescence with central visual disturbance and sparse scalp hair. Reported retinal imaging is lacking, and whether the condition is progressive remains unclear. OBJECTIVE: To investigate a series of patients with HJMD due to biallelic mutations in CDH3 and thereby characterize the disorder. DESIGN, SETTING, AND PARTICIPANTS: Ten patients from 10 families underwent detailed clinical assessment, including serial retinal imaging and electrophysiologic evaluation, at Moorfields Eye Hospital, St James's University Hospital, and Calderdale Royal Infirmary. Patients ranged in age from 3 to 17 years at onset and 5 to 57 years at last assessment. The molecular genetic investigation included bidirectional Sanger sequencing of all exons and intron-exon boundaries of CDH3 and whole-exome sequencing in 2 patients. The study was conducted from June 5, 2013, to January 15, 2016, with final follow-up completed on December 15, 2015. MAIN OUTCOMES AND MEASURES: Results of clinical assessment and molecular genetic testing. RESULTS: All 10 patients (7 male and 3 female) presented with central visual disturbance in childhood and had lifelong sparse scalp hair with normal facial hair. Fundus examination revealed chorioretinal atrophy of the posterior pole contiguous with the disc in all but 1 patient that was associated with marked loss of autofluorescence on fundus autofluorescence imaging. Optical coherence tomography (OCT) demonstrated variable degrees of atrophy of the outer retina, retinal pigment epithelium, and choroid, with outer retinal tubulations frequently observed. One patient had mild disruption of the inner segment ellipsoid band on OCT and additional mild digit abnormalities. Electrophysiologic evaluation in 5 patients demonstrated macular dysfunction with additional mild, generalized retinal dysfunction in 2 patients. Eight patients had more than 1 evaluation; of these, 5 patients showed deterioration of visual acuity over time, 1 patient remained stable, and 2 patients had severe visual loss at presentation that precluded assessment of visual deterioration. The area of atrophy did not progress with time, but retinal thickness decreased on OCT. Electrophysiologic evaluation in 1 patient found deterioration of macular function after 13 years of follow-up, but the mild, generalized photoreceptor dysfunction remained stable. Biallelic mutations were identified in all patients, including 6 novel mutations. CONCLUSIONS AND RELEVANCE: These results suggest that CDH3-related disease is characterized by a childhood-onset, progressive chorioretinal atrophy confined to the posterior pole. The disease is readily distinguished from other juvenile macular dystrophies by the universally thin and sparse scalp hair. Patients may have additional limb abnormalities.