USH2A mutational spectrum causing syndromic and non-syndromic retinal dystrophies in a large cohort of Mexican patients.

Background: Mutations in the USH2A gene are the leading cause of both non-syndromic autosomal recessive retinitis pigmentosa (RP) and Usher syndrome, a syndromic form of RP characterized by retinal dystrophy and sensorineural hearing loss. To contribute to the expansion of the USH2A-related molecular spectrum, the results of genetic screening in a large cohort of Mexican patients are presented. Methods: The study population comprised 61 patients with a clinical diagnosis of either non-syndromic RP (n = 30) or Usher syndrome type 2 (USH2; n = 31) who were demonstrated to carry biallelic pathogenic variants in USH2A in a three-year period. Genetic screening was performed either by gene panel sequencing or by exome sequencing. A total of 72 available first- or second-degree relatives were also genotyped for familial segregation of the identified variants. Results: The USH2A mutational spectrum in RP patients included 39 distinct pathogenic variants, most of them of the missense type. The most common RP-causing variants were p.Cys759Phe (c.2276G>T), p.Glu767Serfs*21 (c.2299delG), and p.Cys319Tyr (c.956G>A), which together accounted for 25% of all RP variants. Novel USH2A mutations included three nonsense, two missense, two frameshift, and one intragenic deletion. The USH2A mutational spectrum in USH2 patients included 26 distinct pathogenic variants, most of them of the nonsense and frameshift types. The most common Usher syndrome-causing variants were p.Glu767Serfs*21 (c.2299delG), p.Arg334Trp (c.1000C>T), and c.12067-2A>G), which together accounted for 42% of all USH2-related variants. Novel Usher syndrome USH2A mutations included six nonsense, four frameshift, and two missense mutations. The c.2299delG mutation was associated with a common haplotype for SNPs located in exons 2-21 of USH2A, indicating a founder mutation effect. Conclusions: Our work expands the USH2A mutational profile by identifying 20 novel pathogenic variants causing syndromic and non-syndromic retinal dystrophy. The prevalent c.2299delG allele is shown to arise from a founder effect. Our results emphasize the usefulness of molecular screening in underrepresented populations for a better characterization of the molecular spectrum of common monogenic diseases.

Clinical-genetic findings in a group of subjects with macular dystrophies due to mutations in rare inherited retinopathy genes.

PURPOSE: To describe the results of clinical and molecular analyses in a group of patients suffering from inherited macular dystrophies, in which next-generation sequencing (NGS) efficiently detected rare causative mutations. METHODS: A total of eight unrelated Mexican subjects with a clinical and multimodal imaging diagnosis of macular dystrophy were included. Visual assessment methods included best corrected visual acuity, color fundus photography, Goldmann visual field tests, kinetic perimetry, dark/light adapted chromatic perimetry, full-field electroretinography, autofluorescence imaging, and spectral domain-optical coherence tomography imaging. Genetic screening was performed by means of whole exome sequencing with subsequent Sanger sequencing validation of causal variants. RESULTS: All patients exhibited a predominantly macular or cone-dominant disease. Patients' ages ranged from 12 to 60 years. Three cases had mutations in genes associated with autosomal dominant inheritance (UNC119 and PRPH2) while the remaining five cases had mutations in genes associated with autosomal recessive inheritance (CNGA3, POC1B, BEST1, CYP2U1, and PROM1). Of the total of 11 different pathogenic alleles identified, three were previously unreported disease-causing variants. CONCLUSIONS: Macular dystrophies can be caused by defects in genes that are not routinely analyzed or not included in NGS gene panels. In this group of patients, whole exome sequencing efficiently detected rare genetic causes of hereditary maculopathies, and our findings contribute to expanding the current knowledge of the clinical and mutational spectrum associated with these disorders.

Clinical, histopathological, and in silico pathogenicity analyses in a pedigree with familial amyloidosis of the Finnish type (Meretoja syndrome) caused by a novel gelsolin mutation.

Purpose: Familial amyloidosis of the Finnish type (FAF) is an inherited amyloidosis arising from mutations in the gelsolin protein (GSN). The disease includes facial paralysis, loose skin, and lattice corneal dystrophy. To date, FAF has been invariably associated with substitution of Asp214 in GSN. We describe the clinical, histopathological, and genetic features of a family with FAF due to a novel GSN mutation. Methods: Five affected adult individuals in a three-generation FAF pedigree were included in the study. Histopathological analysis was performed on an eyelid skin biopsy from one patient. Genetic analysis included next-generation sequencing (NGS) and Sanger sequencing for confirmation of the GSN variant. Several tools for in silico analysis of pathogenicity for the novel variant and to predict the effect of the amino acid replacement on protein stability were used. Results: Three older adult affected patients exhibited corneal lattice dystrophy, cutis laxa, and facultative peripheral neuropathy. Two younger adult individuals presented only with corneal amyloid deposits. NGS identified a heterozygous GSN c.1631T>G transversion, predicting a novel p.Met544Arg mutation. All in silico tools indicated that p.Met544Arg is deleterious for GSN functionality or stability. Conclusions: The results expand the molecular spectrum of GSN-linked systemic amyloidosis. The novel p.Met544Arg pathogenic variant is predicted to affect gelsolin function, presumably by impairing a potential calcium-sensitive, actin-binding region.

Exome sequencing identifies a SREBF1 recurrent ARG557CYS mutation as the cause of hereditary mucoepithelial dysplasia in a family with high clinical variability.

Hereditary mucoepithelial dysplasia (HMD) is an uncommon autosomal dominant disease affecting skin, mucosae, hair, eyes, and lungs. Prominent clinical features include non-scarring alopecia, mucosal erythema, perineal erythematous intertrigo, and involvement of the conjunctival mucosa. To date, 20 familial or sporadic HMD cases have been described, most of them originating from Caucasian ethnic groups. In this study, a novel HMD pedigree, including an affected father and his daughter, is reported. Clinical expression showed significant differences in affected subjects, especially in the distribution and severity of skin lesions. Exome sequencing demonstrated that both affected subjects carried a heterozygous c.1669C>T (p.Arg557Cys) pathogenic variant in the SREBF1 gene. Our results improve the knowledge of the clinical and genetic features of HMD. In addition, a comparative review of the clinical features of all published HMD cases is presented.

Extracranial midline defects in a patient with craniofrontonasal syndrome with a novel EFNB1 mutation.

We report a female patient with craniofrontonasal syndrome (CFNS) who in addition showed other cranial and extracranial midline defects including partial corpus callosum agenesis, ocular melanocytosis, pigmentary glaucoma, duplex collecting system, uterus didelphys, and septate vagina. She was found to have a novel pathogenic variant in exon 5 of EFNB1, c.646G>T (p.Glu216*) predicted to cause premature protein truncation. From our review, we found at least 39 published CFNS patients with extracranial midline defects, comprising congenital diaphragmatic hernia, congenital heart defects, umbilical hernia, hypospadias, and less frequently, sacrococcygeal teratomas, and internal genital anomalies in females. These findings support that the EFNB1 mutations have systemic consequences disrupting morphogenetic events at the extracranial midline. Though these are not rigorously included as midline defects, we found at least 10 CFNS patients with congenital anomalies of the kidney and urinary tract, all females. Additionally, uterus didelphys and ocular melanocytosis observed in our patient are proposed also as a previously unreported EFNB1-related midline defects. In addition, this case may be useful for considering the intentional search for genitourinary anomalies in future patients with CFNS, which will be helpful to define their frequency in this entity.

Retinal phenotypic characterization of patients with ABCA4 retinopathydue to the homozygous p.Ala1773Val mutation.

Purpose: To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods: Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient. Results: Best-corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed. Conclusions: The results indicate that this particular mutation in ABCA4 is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in ABCA4 is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype-phenotype correlations.

Extension of the mutational and clinical spectrum of SOX2 related disorders: Description of six new cases and a novel association with suprasellar teratoma.

SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss-of-function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation-positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow-growing hypothalamo-pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.

PAX6 allelic heterogeneity in Mexican congenital aniridia patients: expanding the mutational spectrum with seven novel pathogenic variants.

IMPORTANCE: The importance of the study was to describe the clinical characteristics and mutational analysis of Mexican patients with aniridia. BACKGROUND: Aniridia is a panocular hereditary eye disease caused by mutations in the PAX6 transcription factor. Mutation detection rate is highly variable ranging from 30% to 90% in different populations. Very few studies have been published about the PAX6 mutational analysis in aniridia patients from Mexico. In order to establish a more representative PAX6 mutational frequency in the country, a cohort of 22 Mexican unrelated aniridia probands were analysed in this study. DESIGN: Case series. PARTICIPANTS: A total of 22 Mexican probands with bilateral isolated aniridia and their available relatives were included. METHODS: Sanger sequencing was used for the mutational analysis of all coding exons and flanking intronic regions of PAX6. MAIN OUTCOME MEASURES: Clinical characteristics and results of PAX6 mutational analysis in probands with aniridia and available family members. RESULTS: Molecular analysis of PAX6 in 22 index cases with aniridia allowed the identification of a total of 16 different mutations. Seven of these pathogenic variants are novel, including c.183C>G, p.(Y61*); c.718delC, p.(R240Efs*3); c.1149_1152delTCAG, p.(P385Wfs*139); c.257_266delAAATAGCCCA, p.(K86Sfs*35); c.836_843dupGCAACACA p.(P282Afs*86); c.1032+2_1032+3insT; and c.141+2T>A. Inter and intrafamilial phenotypic heterogeneity was found. CONCLUSIONS AND RELEVANCE: The mutational diagnostic rate in this series was 77%, which is comparable with reports from other populations. Importantly, no founder mutations were identified in this case series. Our results add 7 novel PAX6 pathogenic variants to the aniridia-related mutational spectrum and reveal considerable PAX6 allelic heterogeneity in this population.

Exome sequencing identifies a de novo frameshift mutation in the imprinted gene ZDBF2 in a sporadic patient with Nasopalpebral Lipoma-coloboma syndrome.

Nasopalpebral lipoma-coloboma syndrome (NPLCS, OMIM%167730) is an uncommon malformation entity with autosomal dominant inheritance characterized by the combination of nasopalpebral lipoma, colobomas in upper and lower eyelids, telecanthus, and maxillary hypoplasia. To date, no genetic defects have been associated with familial or sporadic NPLCS cases and the etiology of the disease remains unknown. In this work, the results of whole exome sequencing in a sporadic NPLCS patient are presented. Exome sequencing identified a de novo heterozygous frameshift dinucleotide insertion c.6245_6246 insTT (p.His2082fs*67) in ZDBF2 (zinc finger, DBF-type containing 2), a gene located at 2q33.3. This variant was absent in parental DNA, in a set of 300 ethnically matched controls, and in public exome variant databases. This is the first genetic variant identified in a NPLCS patient and evidence supporting the pathogenicity of the identified mutation is discussed. © 2016 Wiley Periodicals, Inc.

Clinical and Genetic Findings in Mexican Patients with Duane Anomaly and Radial Ray Malformations/Okihiro Syndrome.

BACKGROUND: Okihiro syndrome is an autosomal-dominant condition characterized by radial ray malformations associated with Duane anomaly and other clinical characteristics. SALL4 mutations have been identified in 80-90% of patients with Duane- Radial ray defects/Okihiro syndrome. We report the clinical findings and results of SALL4 sequencing from a group of Mexican patients with this disorder. OBJECTIVE: Clinical description and identification of SALL4 mutations in Mexican subjects with radial defects and Duane anomaly. MATERIALS AND METHODS: Five unrelated index cases were studied. Complete ophthalmologic and general physical examination was performed in all patients. Polymerase chain reaction amplification and automated nucleotide sequencing of coding exons and intron-exon junctions of SALL4 gene were carried out in genomic DNA. RESULTS: A novel heterozygous deletion was identified in one patient. Intragenic heterozygous single nucleotide polymorphisms on SALL4 gene ruled out deletions of some exons in other affected patients in whom non-pathogenic variants were identified by Sanger sequencing. Likewise, multiplex ligation-dependent probe amplification analysis ruled out large deletions in this gene. CONCLUSION: We observed a low frequency of SALL4 mutations in Mexican patients with clinical criteria of Okihiro syndrome.

Acro-spondylo-pubic dysostosis associated with cataracts, microcephaly, and normal intelligence.

We report on an adult male with normal intelligence who exhibited an unusual combination of microcephaly, dysostoses of limbs, vertebrae, patellae, and pubic bone, camptodactyly of all fingers, and syndactyly of toes, absent nails on thumbs and some fingers, bilateral cataract, cryptorchidism, polythelia, and nipple-like skin pigmentations of shoulders and upper back. We have been unable to find a description of a similar combination of manifestations in literature. The cause of the anomalies remains unknown.

Familial fleck corneal dystrophy caused by complete deletion of the PIKFYVE gene.

BACKGROUND: Fleck corneal dystrophy (FCD) is a rare autosomal dominant disease that affects exclusively the corneal stroma. The disease is caused by heterozygous variants in PIKFYVE, a gene encoding a lipid kinase involved in multiple cellular pathways, primarily participating in membrane dynamics and signaling. This report describes a familial case of FCD caused by a complete deletion of the PIKFYVE gene. MATERIAL AND METHODS: A clinical ophthalmic examination was performed on the proband and family members. Genetic testing included next-generation sequencing (multigene panel), and chromosomal microarray analysis. A quantitative PCR assay was designed in order to segregate the deletion. RESULTS: A 19-year-old male, with no family or personal history of ocular disease, presented for evaluation due to an acute illness consisting of burning, foreign body sensation, and red eye. Slit lamp biomicroscopy revealed bilateral small pterygia and scattered bilateral white opacities in the corneal stroma, a very similar corneal phenotype was found in the 47-year-old father, who was asymptomatic. NGS detected a heterozygous deletion of the entire PIKFYVE coding sequence. CMA in DNA from the propositus indicated a 543 kb deletion in 2q33.3q34 spanning the entire PIKFYVE gene. The deletion was confirmed in the father. CONCLUSIONS: We add to the molecular spectrum of FCD by describing a familial case of a whole PIKFYVE gene deletion in affected subjects. Our findings support that normal expression of PIKFYVE is necessary for corneal keratocytes homeostasis and normal corneal appearance. We conclude that PIKFYVE haploinsufficiency is the molecular mechanism underlying this familial case of FCD.

Identification of Genetic Variants for Diabetic Retinopathy Risk Applying Exome Sequencing in Extreme Phenotypes.

Background: Diabetic retinopathy (DR) risk has been shown to vary depending on ethnic backgrounds, and thus, it is worthy that underrepresented populations are analyzed for the potential identification of DR-associated genetic variants. We conducted a case-control study for the identification of DR-risk variants in Mexican population. Methods: We ascertained 60 type 2 diabetes mellitus (T2DM) patients. Cases (n = 30) were patients with advanced proliferative DR (PDR) with less than 15 years after a T2DM diagnosis while controls (n = 30) were patients with no DR 15 years after the diagnosis of T2DM. Exome sequencing was performed in all patients, and the frequency of rare variants was compared. In addition, the frequency of variants occurring in a set of 169 DR-associated genes were compared. Results: Statistically significant differences were identified for rare missense and splice variants and for rare splice variants occurring more than once in either group. A strong statistical difference was observed when the number of rare missense variants with an aggregated prediction of pathogenicity and occurring more than once in either group was compared (p = 0.0035). Moreover, 8 variants identified more than once in either group, occurring in previously identified DR-associated genes were recognized. The p.Pro234Ser KIR2DS4 variant showed a strong protective effect (OR = 0.04 [0.001-0.36]; p = 0.04). Conclusions: Our study showed an enrichment of rare splice acceptor/donor variants in patients with PDR and identified a potential protective variant in KIR2DS4. Although statistical significance was not reached, our results support the replication of 8 previously identified DR-associated genes.

ABCA4 mutational spectrum in Mexican patients with Stargardt disease: Identification of 12 novel mutations and evidence of a founder effect for the common p.A1773V mutation.

The aim of this study was to assess the mutational spectrum of the ABCA4 gene in a cohort of patients with Stargardt disease from Mexico, a previously uncharacterized population. Clinical diagnosis in each patient was supported by a complete ophthalmological assessment that included visual acuity measurement, a slit lamp examination, a fundus examination and photography, electroretinography, fluorescein angiography, and computerized visual fields testing. Molecular analysis was performed by PCR amplification and direct nucleotide sequence of the 50 exons of the ABCA4 gene in genomic DNA. A total of 31 unrelated subjects with the disease were enrolled in the study. Molecular analysis in the total group of 62 alleles allowed the identification of 46 mutant ABCA4 alleles carrying 29 different pathogenic disease-associated mutations. Two ABCA4 mutant alleles were detected in 20 of the 31 patients (64.5%), a single disease allele was identified in six (19.4%), and no mutant alleles were detected in five of the cases (16.1%). Most patients with two ABCA4 mutations (11/20, 55%) were compound heterozygotes. Twelve variants were novel ABCA4 mutations. Nucleotide substitutions were the most frequent type of variation, occurring in 26 out of 29 (89.7%) different mutations. The two most common mutations in our study were the missense changes p.A1773V and p.G818E, which were identified in eight (17%) and seven (15%) of the total 46 disease-associated alleles, respectively. Haplotype analyses of intragenic SNPs in four subjects carrying the p.A1773V mutation supported a common origin for this mutation. In conclusion, this is the first report of ABCA4 molecular screening in Latin American Stargardt disease patients. Our results expand the mutational spectrum of the disease by adding 12 novel ABCA4 pathogenic variants and support the occurrence of a founder effect for the p.A1773V mutation in the Mexican population. The identification of recurrent mutations in our cohort will direct future ABCA4 molecular screening in patients from this ethnic group.

Nasopalpebral lipoma-coloboma syndrome: clinical, radiological, and histopathological description of a novel sporadic case.

Nasopalpebral lipoma-coloboma syndrome is an extremely uncommon autosomal dominant condition characterized by congenital upper eyelid and nasopalpebral lipomas, colobomata of upper and lower eyelids, telecanthus, and maxillary hypoplasia. A few familial and sporadic cases of this malformation syndrome have been previously reported. Here, the clinical, radiological, and histopathological features of a sporadic Mexican patient with the nasopalpebral lipoma-coloboma syndrome are described. To our knowledge, this is the first time that craniofacial 3D computed tomography imaging was used for a detailed assessment of the facial lipoma.

Learning from history in the midst of the COVID-19: epidemics/pandemics of antiquity up to the fall of the Western Roman Empire.

When humans discovered agriculture and livestock, they ceased to be nomads and began to settle in towns until they created large cities. From the first human settlements in Egypt, Mesopotamia, and the Anatolian Peninsula, populations were exposed and susceptible to new infectious agents, leading to epidemics and pandemics. Great civilizations emerged, such as Egypt, the land of Hatti, Israel, Greece, Carthage, and Rome, among others. Contact between different populations through wars or maritime trade is well documented and has been described as a source of epidemics throughout history. Epidemics described as plagues or pestilences, such as those of Egypt, the Hebrews, or the Hittites, are based on biblical texts or evidence such as tablets or hieroglyphic writings. We also reviewed classical books by authors such as Homer, Aeschylus, Herodotus of Halicarnassus, Thucydides, Diodorus Siculus, Dionysius of Halicarnassus, Titus Livius, Suetonius, and others; and described all epidemics/pandemics chronologically. This article describes the epidemics/pandemics for which there is written evidence from ancient Egypt to the fall of the Roman Empire. We should not be surprised when new epidemics/pandemics appear as causes of political and economic collapse, as this has been common throughout history, decimating, blocking, or even destroying cultures and civilizations repeatedly.

Cuando el hombre descubrió la agricultura y la ganadería, dejó de ser nómada y empezó a asentarse en pueblos hasta crear grandes ciudades. Desde los primeros asentamientos humanos en Egipto, Mesopotamia y la península de Anatolia, las poblaciones estuvieron expuestas y susceptibles a nuevos agentes infecciosos, dando lugar a epidemias y pandemias. Aparecieron grandes civilizaciones como Egipto, la Tierra de Hatti, Israel, Grecia, Cartago y Roma, entre otras. El contacto entre las distintas poblaciones a través de las guerras o el comercio marítimo está muy bien establecido y descrito como focos de epidemias a lo largo de la historia. Las epidemias descritas como plagas o pestilencias, como las que ocurrieron a los egipcios, los judíos, o los hititas, se describen con base en textos bíblicos o mediante evidencias como tablillas o escritos jeroglíficos. También revisamos libros clásicos de autores como Homero, Esquilo, Herodoto de Halicarnaso, Tucídides, Diodoro Sículo, Dionisio de Halicarnaso, Tito Livio, Suetonio, entre otros. Este artículo describe cronológicamente todas las epidemias/pandemias de las que existe evidencia a través de la escritura desde el antiguo Egipto hasta la caída del Imperio Romano. No debemos sorprendernos cuando aparecen nuevas epidemias/pandemias como causantes del colapso político y económico, ya que ha sido algo común a lo largo de la historia, diezmando, bloqueando o incluso destruyendo culturas y civilizaciones reiteradamente.

Novel CHRDL1 mutation causing X-linked megalocornea in a family with mild anterior segment manifestations in carrier females.

PURPOSE: X-linked megalocornea (XMC) is a rare anterior segment malformation characterized by a nonprogressive enlargement of the cornea to 13 mm or greater in the setting of normal intraocular pressure. XMC is caused by mutations in the CHRDL1 gene and it is inherited as an X-linked recessive trait affecting only males. Here, we describe the results of phenotypic and genetic assessment in a novel XMC pedigree. METHODS: Three subjects (a father and his two daughters) underwent a complete clinical and imaging ocular examination including biomicroscopy, fundoscopy, tonometry, visual acuity, Pentacam Scheimpflug imaging, anterior segment Swept Source OCT, and ultrabiomicroscopy. Genetic analysis was performed through whole exome sequencing in 3 family members. Candidate variants were validated by sanger sequencing. RESULTS: The affected father exhibited megalocornea, very deep anterior chambers, retrocorneal pigmentation, iris atrophy, queer iris configuration, extremely open iridocorneal angles, and cataracts. Notably, both daughters showed queer iris configuration and abnormally widely open iridocorneal angles in both eyes. Genetic analysis identified a novel hemizygous c.207+1G>A splicing variant in CHRDL1 in the affected father. Both mildly affected daughters were heterozygous for the pathogenic variant. CONCLUSIONS: Here, we report an additional XMC family due to a novel mutation in the CHRDL1 gene. Mild anterior segment anomalies were observed in two heterozygous carriers demonstrating for the first time a CHRDL1-linked phenotype in females. A detailed comparison of the clinical and genetic features of this pedigree with those observed in previously published XMC cases is also presented.

Expanding the phenotype of gingival fibromatosis-mental retardation-hypertrichosis (Zimmermann-Laband) syndrome.

Zimmermann-Laband syndrome (ZLS) is a rare disorder characterized by gingival fibromatosis, hypertrichosis, intellectual disability, and absence and/or hypoplasia of the nails or terminal phalanges of the hands and feet. The syndromic features of ZLS are highly variable and can overlap with other entities featuring gingival fibrosis. This study describes a patient with ZLS with novel findings, including colpocephaly, hemivertebra, polydactyly, hyperpigmentation, and hemihyperplasia. Thus, the present report expands the phenotypic spectrum of this uncommon syndrome.

Clinical and molecular features of familial and sporadic cases of von Hippel-Lindau disease from Mexico.

BACKGROUND: von Hippel-Lindau disease (VHL) is an uncommon autosomal dominant condition predisposing to the development of tumours in a variety of body organs and caused by germline mutations in VHL, a tumour suppressor gene located on 3p. Up to 60% of VHL patients show ocular involvement with retinal hemangioblastoma being the most common observed lesion. In this study, we describe the clinical and genetic characteristics of two familial and one apparently non-familial case of VHL ascertained at our institution. METHODS: Clinical evaluation included ophthalmologic examination and imaging exams for tumours identification; molecular analysis consisted of PCR amplification of the complete VHL gene coding sequence (three exons) and automated nucleotide sequencing. RESULTS: A total of eight affected subjects were demonstrated to carry a causative mutation in VHL. Affected subjects from family #1 had a c.245G > C change, predicting a p.R82P substitution, affected individuals from family #2 were shown to have a c.266T > C change, leading to a p.L89P missense substitution, whereas the apparently non-familial case had a c.298-299insA mutation. One subject from family #2 was a non-penetrant carrier. No ocular anomalies were found in two adult affected subjects carrying the p.L89P mutation. CONCLUSION: Considerable interfamilial and intrafamilial clinical variability as well as one instance of non penetrance were recorded in these VHL disease cases. Three different mutations were demonstrated, including the c.298-299insA one base insertion, which has been previously described in two unrelated families from our country. Although additional studies are needed, our data suggest that this insertion could be a 'founder' mutation.

Previously undescribed phenotypic findings and novel ACTG1 gene pathogenic variants in Baraitser-Winter cerebrofrontofacial syndrome.

Baraitser-Winter cerebrofrontofacial syndrome is an autosomal dominant disease characterized by multiple congenital abnormalities and intellectual disability, which is caused by mutations in either the ACTB or ACTG1 genes. In this report, we described novel phenotypic findings in two Mexican patients with the disorder in whom two novel ACTG1 mutations (c.176A > G, p.Gln59Arg; and c.608C > T, p.Thr203Met) were identified.