Expanding the phenotype spectrum associated with pathogenic variants in the COL2A1 and COL11A1 genes

We report the clinical findings of 26 individuals from 16 unrelated families carrying variants in the COL2A1 or COL11A1 genes. Using Sanger and next-generation sequencing, 11 different COL2A1 variants (seven novel), were identified in 13 families (19 affected individuals), all diagnosed with Stickler syndrome (STL) type 1. In nine families, the COL2A1 disease-causing variant arose de novo. Phenotypically, we observed myopia (95%) and retinal detachment (47%), joint hyperflexibility (92%), midface retrusion (84%), cleft palate (53%), and various degrees of hearing impairment (50%). One patient had a splenic artery aneurysm. One affected individual carrying pathogenic variant in COL2A1 showed no ocular signs including no evidence of membranous vitreous anomaly. In three families (seven affected individuals), three novel COL11A1 variants were found. The propositus with a de novo variant showed an ultrarare Marshall/STL overlap. In the second family, the only common clinical sign was postlingual progressive sensorineural hearing impairment (DFNA37). Affected individuals from the third family had typical STL2 signs. The spectrum of disease phenotypes associated with COL2A1 or COL11A1 variants continues to expand and includes typical STL and various bone dysplasias, but also nonsyndromic hearing impairment, isolated myopia with or without retinal detachment, and STL phenotype without clinically detectable ocular pathology.     

Homozygous variants in AMPD2 and COL11A1 lead to a complex phenotype of pontocerebellar hypoplasia type 9 and Stickler syndrome type 2

Pontocerebellar hypoplasia type 9 (PCH9) is an autosomal recessive neurodevelopmental disorder caused by pathogenic variants in the AMPD2 gene. We evaluated the son of a consanguineous couple who presented with profound hypotonia and global developmental delay. Other features included sensorineural hearing loss, asymmetric astigmatism, and high myopia. Clinical whole‐exome sequence analysis identified a homozygous missense variant in AMPD2 (NM_001257360.1:c.2201C > T, p.[Pro734Leu]) that has not been previously reported. Given the strong phenotypic overlap with PCH9, including the identification of the typical “Figure 8” appearance of the brainstem on neuroimaging, we suspect this variant was causative of the neurodevelopmental disability in this individual. An additional homozygous nonsense variant in COL11A1 (NM_001854.4:c.1168G > T, p.[Glu390Ter]) was identified. Variants in this alternatively spliced region of COL11A1 have been identified to cause an autosomal recessive form of Stickler syndrome type 2 characterized by sensorineural hearing loss and eye abnormalities, but without musculoskeletal abnormalities. The COL11A1 variant likely also contributed to the individual's phenotype, suggesting two potentially relevant genetic findings. This challenging case highlights the importance of detailed phenotypic characterization when interpreting whole exome data.     

Stickler and branchio-oto-renal syndromes in a patient with mutations in EYA1 and COL2A1 genes

Branchio-oto-renal (BOR) and Stickler (STL) syndromes are disorders that include hearing loss among their clinical features. STL syndrome type I (STL1) is a combination of ophthalmic, orofacial, articular, and auditory manifestations, caused by mutations in the COL2A1 . BOR syndrome is an autosomal dominant trait encompassing branchial, otic and renal anomalies because of mutations in EYA1 , SIX1 and SIX5 . In this study, we have clinically and genetically diagnosed a proband that displayed STL1 and BOR syndromes. This patient and his younger brother exhibited hearing loss and cleft palate. Both siblings and their mother also showed myopia, congenital non-progressive vitreous anomaly and a flat face. Taken together, these clinical features are consistent with the diagnosis of a familial case of STL. Sequence analysis revealed in the three patients a novel COL2A1 mutation (c.1468_1475delinsT) that accounted for a STL1 phenotype. The proband also displayed pre-auricular pits, branchial fistulae and renal agenesis that define BOR syndrome. Interestingly, this patient carries an EYA1 mutation, p.R328X, which was not present in the two other patients or in his healthy father, supporting that the mutation arose de novo . In conclusion, this report highlights the importance of molecular testing and detailed clinical evaluation for the diagnosis of syndromes with overlapping phenotypic features.     

Stickler syndrome and the vitreous phenotype: mutations in COL2A1 and COL11A1

Stickler syndrome is a dominantly inherited disorder affecting the fibrillar type II/XI collagen molecules expressed in vitreous and cartilage. Mutations have been found in COL2A1, COL11A1 and COL11A2. It has a highly variable phenotype that can include midline clefting, hearing loss, premature osteoarthritis, congenital high myopia and blindness through retinal detachment. Although the systemic phenotype is highly variable, the vitreous phenotype has been used successfully to differentiate between patients with mutations in these different genes. Mutations in COL2A1 usually result in a congenital membranous vitreous anomaly. In contrast mutations in COL11A1 result in a different vitreous phenotype where the lamellae have an irregular and beaded appearance. However, it is now apparent that a new sub‐group of COL2A1 mutations is emerging that result in a different phenotype with a hypoplastic vitreous that fills the posterior chamber of the eye, and is either optically empty or has sparse irregular lamellae. Here we characterise a further 89 families with Stickler syndrome or a type II collagenopathy, and correlate the mutations with the vitreous phenotype. We have identified 57 novel mutations including missense changes in both COL2A1 and COL11A1 and have also detected two cases of complete COL2A1 gene deletions using MLPA. ©2010 Wiley‐Liss, Inc.     

A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome

Stickler syndrome is characterized by ocular, auditory, skeletal, and orofacial abnormalities. We describe a family with autosomal recessive Stickler syndrome. The main clinical findings consisted of high myopia, vitreoretinal degeneration, retinal detachment, hearing loss, and short stature. Affected family members were found to have a homozygous loss‐of‐function mutation in COL9A2, c.843_c.846 + 4del8. A family with autosomal recessive Stickler syndrome was previously described and found to have a homozygous loss‐of‐function mutation in COL9A1. COL9A1, COL9A2, and COL9A3 code for collagen IX. All three collagen IX α chains, α1, α2, and α3, are needed for formation of functional collagen IX molecule. In dogs, two causative loci have been identified in autosomal recessive oculoskeletal dysplasia. This dysplasia resembles Stickler syndrome. Recently, homozygous loss‐of‐function mutations in COL9A2 and COL9A3 were found to co‐segregate with the loci. Together the data from the present study and the previous studies suggest that loss‐of‐function mutations in any of the collagen IX genes can cause autosomal recessive Stickler syndrome. © 2011 Wiley‐Liss, Inc.     

Facio-oculo-acoustico-renal (FOAR) syndrome: Case report and review

We report on an 11-year-old boy with distinct facial anomalies, iris coloboma, iris hypoplasia, cataract, high myopia, retinal detachment, moderate sensorineural hearing loss, and proteinuria. He appears to have the facio-oculo-acoustico-renal (FOAR) syndrome, a rare familial disorder reported only 4 times previously. In contrast to the other patients, he has normal intellect. Am. J. Med. Genet. 69:45–49, 1997. © 1997 Wiley-Liss, Inc.     

Missense and nonsense mutations in the alternatively-spliced exon 2 of COL2A1 cause the ocular variant of Stickler syndrome

Stickler syndrome type I (STL1) is a phenotypically heterogeneous disorder characterized by ocular and extraocular features. It is caused by null-allele mutations in the COL2A1 gene that codes for procollagen II. COL2A1 precursor mRNA undergoes alternative splicing, resulting in two isoforms, a long form including exon 2 (type IIA isoform) and a short form excluding exon 2 (type IIB isoform). The short form is predominantly expressed by differentiated chondrocytes in adult cartilage, and the long form in chondroprogenitor cells during early development and in the vitreous of the eye, which is the only adult tissue containing procollagen IIA. Recent evidence indicates that due to the tissue-specific expression of these two isoforms, premature termination codon mutations in exon 2 cause Stickler syndrome with minimal or no extraocular manifestations. We describe here two mutations in exon 2 of COL2A1 in three patients with predominantly ocular Stickler syndrome: Cys64Stop in two patients, and a novel structural mutation, Cys57Tyr, in one patient. RT-PCR of total lymphoblast RNA from one patient with the Cys64Stop mutation revealed that only the normal allele of the IIA form was present, indicating that the mutation resulted either in complete loss of the allele by nonsense-mediated mRNA decay or by skipping of exon 2 via nonsense-mediated altered splicing, resulting in production of the type IIB isoform. The results of COL2A1 minigene expression studies suggest that both Cys64Stop and Cys57Tyr alter positive cis regulatory elements for splicing, resulting in a lower IIA:IIB ratio.     

Clinical evaluation and COL2A1 gene analysis in 21 Brazilian families with Stickler syndrome: identification of novel mutations, further genotype/phenotype correlation, and its implications for the diagnosis

We present clinical and molecular evaluation from a large cohort of patients with Stickler syndrome: 78 individuals from 21 unrelated Brazilian families. The patients were selected in a Hospital with a craniofacial dysmorphology assistance service and clinical diagnosis was based on the presence of cleft palate associated to facial and ocular anomalies of Stickler syndrome. Analysis of COL2A1 gene revealed 9 novel and 4 previously described pathogenic mutations. Except for the mutation c.556G>T (p.Gly186X), all the others were located in the triple helical domain. We did not find genotype/phenotype correlation in relation to type and position of the mutation in the triple helical domain. However, a significantly higher proportion of myopia in patients with mutations located in this domain was observed in relation to those with the mutation in the non-tripe helical domain (c.556G>T; P < 0.04). A trend towards a higher prevalence of glaucoma, although not statistically significant, was observed in the presence of the mutation c.556G>T. It is possible that this mutation alters the splicing of the mRNA instead of only creating a premature stop codon and therefore it can lead to protein products of different ocular effects. One novel DNA variation (c.1266+7G>C) occurs near a splice site and it was observed to co-segregate with the phenotype in one of the two families with this DNA variation. As in silico analysis predicted that the c.1266+7G>C DNA variation can affect the efficiency of the splicing, we still cannot rule it out as non-pathogenic. Our study also showed that ascertainment through cleft palate associated to other craniofacial signs can be very efficient for identification of Stickler syndrome patients. Still, high frequency of familial cases and high frequency of underdevelopment of distal lateral tibial epiphyses observed in our patients suggested that the inclusion of this information can improve the clinical diagnosis of Stickler syndrome.     

A novel autosomal recessive GJB2‐associated disorder: Ichthyosis follicularis,bilateral severe sensorineural hearing loss,and punctate palmoplantar keratoderma

Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. The pathogenicity and consequences of mutations were studied in the Xenopus oocyte expression system and by molecular modeling analysis. Compound heterozygous mutations in the GJB2 gene were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. The p.Asn176Asp missense mutation was demonstrated to significantly reduce the cell–cell gap junction channel activity and increase the nonjunctional hemichannel activity in the Xenopus oocyte expression system. Molecular modeling analyses of the mutant Cx26 protein revealed significant changes in the structural characteristics and electrostatic potential of the Cx26, either in hemichannel or gap junction conformation. Thus, association of a new syndrome of an autosomal recessive disorder of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma with mutations in GJB2, expands the phenotypic spectrum of the GJB2‐associated disorders. The findings attest to the complexity of the clinical consequences of different mutations in GJB2.     

Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymüller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome)

The original patient with the Weissenbacher-Zweymüller syndrome was analyzed for mutations in two candidate genes expressed in cartilage (COL2A1 and COL11A2). No mutations were found in the COL2A1 gene but the COL11A2 gene contained a single-base mutation that converted a codon for an obligate glycine to a codon for glutamate at position α2-955 (G955E). The results here and those published previously indicate that the Weissenbacher-Zweymüller syndrome (heterozygous OSMED), nonocular Stickler syndrome, and homozygous OSMED are all caused by mutations in the COL11A2 gene. Am. J. Med. Genet. 80:115–120, 1998. © 1998 Wiley-Liss, Inc.     

High prevalence of V37I genetic variant in the connexin-26 (GJB2) gene among non-syndromic hearing-impaired and control Thai individuals

Hearing loss is highly prevalent with a worldwide incidence of 1-2 per 1000 newborns. Several previous studies have demonstrated that mutations of connexin 26 (Cx26 or GJB2) are responsible for most cases of the recessive non-syndromic sensorineural hearing loss (NSSHL). Certain mutations have been described frequently among various populations, which include 35delG, 167delT, and 235delC. Recently, a missense mutation, V37I, was reported as a pathogenic change in East Asian affected individuals. To identify genetic variants associated with NSSHL in Thai population, we performed mutation analysis of Cx26 in 166 unrelated probands with NSSHL and 205 controls. We identified seven novel genetic variants in Cx26. We also identified a high prevalence of the V37I mutation among both affected probands (11.1%) and control subjects (8.5%), which suggests that the pathologic role of V37I may be modified by other genes. Our data support previous studies that show heterogeneity in the frequencies and types of mutations in Cx26 within populations and among ethnicities and that before clinical significance and causality can be attributed to a genetic variant, functional characterization is necessary.     

The human α2(IV) collagen gene, COL4A2, is syntenic with the α1(IV) gene, COL4A1, on chromosome 13

We have previously assigned the gene for the α l chain of type IV collagen to chromosome 13. In this report we show that the gene coding for the second chain of this heterotrimer is on the same chromosome. This is the first example of the genes for both chains of one collagen molecule being syntenic.     

Extension of the clinical and molecular phenotype of DIAPH1‐associated autosomal dominant hearing loss (DFNA1)

In about 20% of non‐syndromic hearing loss (NSHL) cases, inheritance is autosomal dominant (ADNSHL). DIAPH1 mutations define the ADNSHL locus DFNA1. We identified two new families with heterozygous truncating DIAPH1 mutations (p.Ala1210Serfs*31 and p.Arg1213*). In contrast to the extensively studied original DFNA1 family, hearing loss was not confined to low frequencies, but congenital manifestation and rapid progression were confirmed. In line with a recent unrelated study, we identified an association with thrombocytopenia, reclassifying DFNA1 as a syndrome. Consequently, we suggest to include the blood count into the initial clinical workup of patients with autosomal dominant hearing loss to guide the genetic diagnosis. We provide the first data on DIAPH1 expression in the organ of Corti, where it localizes to the inner pillar cells, at the base of the outer hair cells. Homozygous truncating DIAPH1 mutations located N‐terminally to the DFNA1 mutations have recently been identified in autosomal recessive microcephaly. It is therefore noteworthy that we found DIAPH1 expression also in spiral ganglion neurons and in the barrier between the myelinating glia of the peripheral nervous system and oligodendrocytes that form the myelinating glia of the central nervous system (CNS).     

Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients

Osteogenesis imperfecta (OI) is caused by mutations in COL1A1 and COL1A2 that code for the alpha1 and alpha2 chains of type I collagen. Phenotypes correlate with the mutation types in that COL1A1 null mutations lead to OI type I, and structural mutations in alpha1(I) or alpha2(I) lead to more severe OI types (II-IV). However, correlative analysis between mutation types and OI associated hearing loss has not been previously performed. A total of 54 Finnish OI patients with previously diagnosed hearing loss or age 35 or more years were analyzed here for mutations in COL1A1 or COL1A2. Altogether 49 mutations were identified, of which 41 were novel. The 49 mutations represented the molecular genetic background of 41.1% of the Finnish OI population. A total of 38 mutations were in COL1A1 and 11 were in COL1A2. Of these, 16 were glycine substitutions and 16 were splicing mutations in alpha1(I) or alpha2(I). In addition, 17 null allele mutations were detected in COL1A1. A total of 32 patients (65.3%) with a mutation had hearing loss. That is slightly more than in our previous population study on Finnish adults with OI (57.9%). The association between the mutation types and OI type was statistically evident. Patients with COL1A1 mutations more frequently had blue scleras than those with COL1A2 mutations. In addition, patients with COL1A2 mutations tended to be shorter than those with COL1A1 mutations. However, no correlation was found between the mutated gene or mutation type and hearing pattern. These results suggest that the basis of hearing loss in OI is complex, and it is a result of multifactorial, still unknown genetic effects.     

Update of spectrum c.35delG and c.‐23+1G>A mutations on the GJB2 gene in individuals with autosomal recessive nonsyndromic hearing loss

Hearing loss (HL) is the most common birth defect and the most prevalent sensorineural condition worldwide. It is associated with more than 1,000 mutations in at least 90 genes. Mutations of the gap junction beta‐2 protein (GJB2) gene located in the nonsyndromic hearing loss and deafness (DFNB1) locus (chromosome 13q11‐12) are the main causes of autosomal recessive nonsyndromic hearing loss worldwide, but important differences exist between various populations. In the present article, two common mutations of the GJB2 gene are compared for ethnic‐specific allele frequency, their function, and their contribution to genetic HL in different populations. The results indicated that mutations of the GJB2 gene could have arisen during human migration. Updates on the spectrum of mutations clearly show that frequent mutations in the GJB2 gene are consistent with the founder mutation hypothesis.     

COL1A2 (type I collagen) polymorphisms in the Colorado Indians of Ecuador

Background: EcoRI, MspI and RsaI restriction fragment length polymorphisms (RFLPs) of the COL1A2 (type I collagen) gene are proving to be extremely informative markers for describing human populations; therefore they hold considerable potential for anthropogenetic research.

Aim: The objective of this study was to characterize at the DNA level the Colorado Indians from Ecuador, for whom only blood group frequency information is available, and to investigate their relationships with the Cayapa—another Ecuadoran Native American group belonging to the same linguistic affiliation—and other world populations.

Subjects and methods: Colorado Indians (n?=?80) were analysed for the three anthropologically informative RFLPs of the COL1A2 gene. To better define the genetic relationship between this group and other populations, principal component analysis (PCA) was performed and genetic distances were estimated. Population genetic structure was tested through analysis of molecular variance (AMOVA) by comparing haplotype frequencies.

Results: COL1A2 allele and haplotype frequencies showed a certain degree of heterogeneity between the two Chibchan populations of Ecuador. The AMOVA test detected a significant level of differentiation (Fst?=?0.034,

p?=?0.0049) between Colorado and Cayapa Indians. PC and genetic distance analyses showed a clear-cut separation between African and non-African populations; within the latter, the two Native American groups were differentiated from each other.

Conclusions: The present findings suggest the presence of a low level of genetic relatedness between the Colorado and the Cayapa, despite their supposed common ethnogenesis. This confirms what has been inferred from other genetic data about the high degree of heterogeneity among Native Americans, even within the same linguistic branch, thus supporting the existence of genetic sub-structure within the central and southern American populations.

Résumé. Arrière plan: Les polymorphismes de longueurs de fragments de restriction (RFLP) du gène COL1A2 (collagène de type 1) apparaissent comme des marqueurs humains extrêmement informatifs; ils présentent donc un intérêt potentiel considérable pour les recherches d’anthropogénétique.

But: Cette étude caractérise le niveau d’ADN des indiens Colorado de l’Equateur, pour lesquels est seulement disponible l’information sur les fréquences des groupes sanguins, et examine leur relation avec un autre groupe amérindien d’Equateur de même affiliation linguistique, les indiens Cayapa, ainsi qu’avec d’autres populations.

Sujets et méthodes: 80 indiens Colorado ont été analysés par rapport aux trois RFLP du gène COL1A2 anthropologiquement informatifs. Afin de mieux définir les relations génétiques de ce groupe avec d’autres populations, on a effectué une analyse en composantes principales et estimé des distances génétiques. La structure génétique de la population a été éprouvée par analyse de variance moléculaire (AMOVA) en comparant les fréquences haplotypiques.

Résultats: L’allèle COLA12 et les fréquences haplotypiques indiquent un certain degré d’hétérogénéité des deux populations Chibchan d’Equateur. Le test AMOVA détecte un niveau significatif de différenciation (Fst?=?0,034 p?=?0.0049) entre indiens Colorado et Cayapa. Les analyses de CP et de distances génétiques montrent une séparation nette entre populations africaines et non africaines. Parmi ces dernières, les deux groupes amérindiens se séparent l’un de l’autre.

Conclusion: Ces résultats suggèrent une relation génétique faible entre Colorado et Cayapa, en dépit de leur ethnogenèse supposée commune. Ils confirment ce qui a été inféré à partir d’autres données génétiques, concernant le haut degré d’hétérogénéité des amérindiens, même au sein d’une même branche linguistique, ce qui soutient l’hypothèse de l’existence d’une sous structure génétique dans les populations amérindiennes du centre et du sud des continents américains.

Zusammenfassung. Hintergrund: EcoRI-, MspI- und RsaI-Restriktionsfragmentlängen-Polymorphismen (restriction fragment length polymorphisms, RFLPs) des COL1A2-(Typ I-Kollagen)-Gens erweisen sich als besonders informative Marker, um menschliche Populationen zu beschreiben; dadurch haben sie ein beträchtliches Potenzial für anthropogenetische Untersuchungen.

Ziel: Das Ziel dieser Studie war, Colorado-Indianer aus Ecuador, für die nur Information betreffend Blutgruppenhäufigkeit vorhanden ist, auf DNS-Ebene zu charakterisieren und ihre Beziehung mit den Cayapa – einer anderen eingeborenen Amerikanischen Bevölkerung Ecuadors, die miteinander sprachlich verwandt sind – und anderen Populationen dieser Welt zu untersuchen.

Probanden und Methoden: Colorado-Indianer (n?=?80) wurden betreffend drei anthropologisch informative RFLPs des COL1A2-Gens untersucht. Um die genetische Beziehung zwischen dieser Gruppe und anderen Populationen besser definieren zu können, wurden Hauptkomponenten-Analysen (principal component analysis, PCA) gerechnet und genetische Distanzen bestimmt. Die genetische Struktur der Population wurde mittels einer Analyse der molekularen Varianz (analysis of molecular variance, AMOVA) durch Vergleich von Haplotyp-Häufigkeiten getestet.

Ergebnisse: COL1A2-Allel- und Haplotyp-Häufigkeiten zeigten ein gewisses Maß an Heterogenität zwischen den beiden Chibchan Populationen aus Ecuador. Der AMOVA-Test zeigte einen signifikanten Unterschied (Fst = 0,034, p = 0,0049) zwischen Colorado- und Cayapa-Indianern. Hauptkomponenten-Analysen und die Analyse der genetischen Distanz zeigten eine klare Trennung zwischen Afrikanern und nicht-Afrikanischen Populationen; bei den letzteren ließen sich die beiden eingeborenen Amerikanischen Populationen voneinander unterscheiden.

Zusammenfassung: Die vorliegenden Ergebnisse legen nahe, dass zwischen den Colorado und den Cayapa, trotz ihres bisher vermuteten gemeinsamen ethnischen Ursprungs, nur ein niedriges Ausmaß an genetischer Verwandtschaft besteht. Das bestätigt, was schon aus anderen genetischen Untersuchungsbefunden über den hohen Grad an Heterogenität unter eingeborenen Amerikanischen Völkern – selbst innerhalb derselben Sprachenfamilie – geschlossen worden ist, und bestätigt damit das Vorhandensein von genetischen Unterstrukturen bei Mittel- und Südamerikanischen Völkern.

Resumen. Antecedentes: Se ha comprobado que los polimorfismos de longitud de los fragmentos de restricción (RFLPs) EcoRI, MspI y RsaI, son marcadores muy informativos para describir a las poblaciones humanas; por tanto, tienen un potencial considerable para la investigación antropogenética.

Objetivos: El objetivo de este estudio fue caracterizar a nivel del ADN a los indios Colorado de Ecuador, de los que solo se dispone de información sobre las frecuencias de grupos sanguíneos, e investigar sus relaciones con los Cayapa, otro grupo Americano nativo de Ecuador que pertenece al mismo grupo lingüístico, y con otras poblaciones mundiales.

Sujetos y métodos: Se analizaron indios Colorado (n?=?80) para los tres RFLPs del gen COL1A2, antropológicamente informativos. Para definir mejor la relación genética entre este grupo y otras poblaciones, se realizó un análisis en componentes principales (ACP) y se estimaron las distancias genéticas. La estructura genética de la población se comprobó mediante un análisis molecular de la varianza (AMOVA) comparando frecuencias de haplotipos.

Resultados: El alelo COL1A2 y las frecuencias haplotípicas mostraron un cierto grado de heterogeneidad entre las dos poblaciones Chibchan de Ecuador. El test AMOVA detectó un nivel de diferenciación significativo (Fst?=?0,034, p?=?0,0049) entre los indios Colorado y Cayapa. Los análisis PC y de distancia genética mostraron una separación neta entre las poblaciones Africanas y no Africanas; dentro de estas últimas, los análisis diferenciaron a los dos grupos Americanos nativos.

Conclusión: Los resultados actuales sugieren la presencia de un bajo nivel de relación genética entre los indios Colorado y los Cayapa, a pesar de su supuesta etnogénesis común. Esto confirma lo ya inferido a partir de otros datos genéticos sobre el elevado grado de heterogeneidad entre los Americanos nativos, incluso dentro de la misma rama lingüística, y apoya la existencia de una subestructura genética dentro de las poblaciones centroamericanas y sudamericanas.     

A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen

Stickler syndrome (hereditary arthro-ophthalmopathy) is the commonest inherited cause of retinal detachment and one of the commonest autosomal dominant connective tissue dysplasias. There is clinical and locus heterogeneity with about two thirds of families linked to the gene encoding type II procollagen (COL2A1). Families with Sticklers syndrome type 1 have a characteristic congenital vitreous anomaly and are linked without recombination to markers at the COL2A1 locus. In contrast families with the type 2 variety have a different vitreo- retinal phenotype and are not linked to the COL2A1 gene. Type XI collagen is a quantitatively minor fibrillar collagen related to type V collagen and associated with the more abundant type II collagen fibrils. A mutation in COL11A2, the gene for alpha 2 (XI) procollagen, has recently been found in a family described as having Stickler syndrome, although there was no ocular involvement. Here we show for the first time that a family with the full Type 2 Stickler syndrome including vitreous and retinal abnormalities is linked to the COL11A1 gene and characterise the mutation as a Glycine to Valine substitution at position 97 of the triple helical domain caused by a single base G-- >T mutation. These results are the first to provide confirmation that type XI collagen is an important structural component of human vitreous. They also support previous work suggesting that mutations in the genes encoding collagen XI can give rise to some manifestations of Stickler syndrome, but of these, only mutations in COL11A1 will give the full syndrome including the vitreo-retinal features.      

Extending the phenotype associated with the CSNK2A1‐related Okur–Chung syndrome—A clinical study of 11 individuals

Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur–Chung neurodevelopmental syndrome. More recently, through trio‐based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome.