Human genetics of face recognition: discovery of MCTP2 mutations in humans with face blindness (congenital prosopagnosia).

Face recognition is important for both visual and social cognition. While prosopagnosia or face blindness has been known for seven decades and face-specific neurons for half a century, the molecular genetic mechanism is not clear. Here we report results after 17 years of research with classic genetics and modern genomics. From a large family with 18 congenital prosopagnosia (CP) members with obvious difficulties in face recognition in daily life, we uncovered a fully cosegregating private mutation in the MCTP2 gene which encodes a calcium binding transmembrane protein expressed in the brain. After screening through cohorts of 6589, we found more CPs and their families, allowing detection of more CP associated mutations in MCTP2. Face recognition differences were detected between 14 carriers with the frameshift mutation S80fs in MCTP2 and 19 noncarrying volunteers. Six families including one with 10 members showed the S80fs-CP correlation. Functional magnetic resonance imaging found association of impaired recognition of individual faces by MCTP2 mutant CPs with reduced repetition suppression to repeated facial identities in the right fusiform face area. Our results have revealed genetic predisposition of MCTP2 mutations in CP, 76 years after the initial report of prosopagnosia and 47 years after the report of the first CP. This is the first time a gene required for a higher form of visual social cognition was found in humans.

Expanding the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to XX gonadal dysgenesis.

Homozygous variants in PPP2R3C have been reported to cause a syndromic 46,XY complete gonadal dysgenesis phenotype with extragonadal manifestations (GDRM, MIM# 618419) in patients from four unrelated families, whereas heterozygous variants have been linked to reduced fertility with teratozoospermia (SPGF36, MIM# 618420) in male carriers. We present eight patients from four unrelated families of Turkish and Indian descent with three different germline homozygous PPP2R3C variants including a novel in-frame duplication (c.639_647dupTTTCTACTC, p.Ser216_Tyr218dup). All patients exhibit recognizable facial dysmorphisms allowing gestalt diagnosis. In two 46,XX patients with hypergonadotropic hypogonadism and nonvisualized gonads, primary amenorrhea along with absence of secondary sexual characteristics and/or unique facial gestalt led to the diagnosis. 46,XY affected individuals displayed a spectrum of external genital phenotypes from ambiguous genitalia to complete female. We expand the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to both XY and XX gonadal dysgenesis. Our findings supported neither ocular nor muscular involvement as major criteria of the syndrome. We also did not encounter infertility problems in the carriers. Since both XX and XY individuals were affected, we hypothesize that PPP2R3C is essential in the early signaling cascades controlling sex determination in humans.

Face Processing in Developmental Prosopagnosia: Altered Neural Representations in the Fusiform Face Area.

Rationale: Face expertise is a pivotal social skill. Developmental prosopagnosia (DP), i.e., the inability to recognize faces without a history of brain damage, affects about 2% of the general population, and is a renowned model system of the face-processing network. Within this network, the right Fusiform Face Area (FFA), is particularly involved in face identity processing and may therefore be a key element in DP. Neural representations within the FFA have been examined with Representational Similarity Analysis (RSA), a data-analytical framework in which multi-unit measures of brain activity are assessed with correlation analysis. Objectives: Our study intended to scrutinize modifications of FFA-activation during face encoding and maintenance based on RSA. Methods: Thirteen participants with DP (23-70 years) and 12 healthy control subjects (19-62 years) participated in a functional MRI study, including morphological MRI, a functional FFA-localizer and a modified Sternberg paradigm probing face memory encoding and maintenance. Memory maintenance of one, two, or four faces represented low, medium, and high memory load. We examined conventional activation differences in response to working memory load and applied RSA to compute individual correlation-matrices on the voxel level. Group correlation-matrices were compared via Donsker's random walk analysis. Results: On the functional level, increased memory load entailed both a higher absolute FFA-activation level and a higher degree of correlation between activated voxels. Both aspects were deficient in DP. Interestingly, control participants showed a homogeneous degree of correlation for successful trials during the experiment. In DP-participants, correlation levels between FFA-voxels were significantly lower and were less sustained during the experiment. In behavioral terms, DP-participants performed poorer and had longer reaction times in relation to DP-severity. Furthermore, correlation levels were negatively correlated with reaction times for the most demanding high load condition. Conclusion: We suggest that participants with DP fail to generate robust and maintained neural representations in the FFA during face encoding and maintenance, in line with poorer task performance and prolonged reaction times. In DP, alterations of neural coding in the FFA might therefore explain curtailing in working memory and contribute to impaired long-term memory and mental imagery.

Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome.

BACKGROUND: Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP). METHODS: Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome. RESULTS: A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome. CONCLUSION: Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.

Neoplasia in Cri du Chat Syndrome from Italian and German Databases.

Cri du Chat syndrome (CdC) is a chromosomal abnormality (deletion of short arm of chromosome 5) associated with intellectual disability and typical anatomical abnormalities. Research up to now focuses on the management of the disease during childhood. The longer lifespan of these patients warrants deeper investigations of how and if aging could be affected by the syndrome. We decided to focus on the association of the disease with proliferative disorders. Data on proliferative disorders in a cohort of 321 patients from Italian and German Cri du Chat databases were collected. A neoplasia was present in four patients (age 10-50 yrs), and a fifth patient developed a cholesteatoma during childhood. It is of interest that two cases had an early onset of the neoplasia as compared to the expected age of development in the general population. The chromosome region deleted in 5p does not contain genes whose haploinsufficiency is a well-known main cause of the proliferative disorders observed. We nonetheless believe that reporting even sporadic cases of proliferative disorders in CdC patients may increase our knowledge as to the natural history of the disease. In conclusion, available information suggests that surveillance for cancer development in CdC can follow the guidelines for the general population.

Face Perception and Test Reliabilities in Congenital Prosopagnosia in Seven Tests.

Congenital prosopagnosia, the innate impairment in recognizing faces, is a very heterogeneous disorder with different phenotypical manifestations. To investigate the nature of prosopagnosia in more detail, we tested 16 prosopagnosics and 21 controls with an extended test battery addressing various aspects of face recognition. Our results show that prosopagnosics exhibited significant impairments in several face recognition tasks: impaired holistic processing (they were tested amongst others with the Cambridge Face Memory Test (CFMT)) as well as reduced processing of configural information of faces. This test battery also revealed some new findings. While controls recognized moving faces better than static faces, prosopagnosics did not exhibit this effect. Furthermore, prosopagnosics had significantly impaired gender recognition-which is shown on a groupwise level for the first time in our study. There was no difference between groups in the automatic extraction of face identity information or in object recognition as tested with the Cambridge Car Memory Test. In addition, a methodological analysis of the tests revealed reduced reliability for holistic face processing tests in prosopagnosics. To our knowledge, this is the first study to show that prosopagnosics showed a significantly reduced reliability coefficient (Cronbach's alpha) in the CFMT compared to the controls. We suggest that compensatory strategies employed by the prosopagnosics might be the cause for the vast variety of response patterns revealed by the reduced test reliability. This finding raises the question whether classical face tests measure the same perceptual processes in controls and prosopagnosics.

MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development.

Corrigendum: Do congenital prosopagnosia and the other-race effect affect the same face recognition mechanisms?

[This corrects the article on p. 759 in vol. 8, PMID: 25324757.].

Skeletal dysplasia in a consanguineous clan from the island of Nias/Indonesia is caused by a novel mutation in B3GAT3.

We describe a large family with disproportionate short stature and bone dysplasia from Nias in which we observed differences in severity when comparing the phenotypes of affected individuals from two remote branches. We conducted a linkage scan in the more severely affected family branch and determined a critical interval of 4.7 cM on chromosome 11. Sequencing of the primary candidate gene TBX10 did not reveal a disease-causing variant. When performing whole exome sequencing we noticed a homozygous missense variant in B3GAT3, c.419C>T [p.(Pro140Leu)]. B3GAT3 encodes ß-1,3-glucuronyltransferase-I (GlcAT-I). GlcAT-I catalyzes an initial step of proteoglycan synthesis and the mutation p. (Pro140Leu) lies within the donor substrate-binding subdomain of the catalytic domain. In contrast to the previously published mutation in B3GAT3, c.830G>A [p.(Arg277Gln)], no heart phenotype could be detected in our family. Functional studies revealed a markedly reduced GlcAT-I activity in lymphoblastoid cells from patients when compared to matched controls. Moreover, relative numbers of glycosaminoglycan (GAG) side chains were decreased in patient cells. We found that Pro140Leu-mutant GlcAT-I cannot efficiently transfer GlcA to the linker region trisaccharide. This failure results in a partial deficiency of both chondroitin sulfate and heparan sulfate chains. Since the phenotype of the Nias patients differs from the Larsen-like syndrome described for patients with mutation p.(Arg277Gln), we suggest mutation B3GAT3:p.(Pro140Leu) to cause a different type of GAG linkeropathy showing no involvement of the heart.

A family at risk: congenital prosopagnosia, poor face recognition and visuoperceptual deficits within one family.

Congenital prosopagnosia (CP) describes a severe face processing impairment despite intact early vision and in the absence of overt brain damage. CP is assumed to be present from birth and often transmitted within families. Previous studies reported conflicting findings regarding associated deficits in nonface visuoperceptual tasks. However, diagnostic criteria for CP significantly differed between studies, impeding conclusions on the heterogeneity of the impairment. Following current suggestions for clinical diagnoses of CP, we administered standardized tests for face processing, a self-report questionnaire and general visual processing tests to an extended family (N=28), in which many members reported difficulties with face recognition. This allowed us to assess the degree of heterogeneity of the deficit within a large sample of suspected CPs of similar genetic and environmental background. (a) We found evidence for a severe face processing deficit but intact nonface visuoperceptual skills in three family members - a father and his two sons - who fulfilled conservative criteria for a CP diagnosis on standardized tests and a self-report questionnaire, thus corroborating findings of familial transmissions of CP. (b) Face processing performance of the remaining family members was also significantly below the mean of the general population, suggesting that face processing impairments are transmitted as a continuous trait rather than in a dichotomous all-or-nothing fashion. (c) Self-rating scores of face recognition showed acceptable correlations with standardized tests, suggesting this method as a viable screening procedure for CP diagnoses. (d) Finally, some family members revealed severe impairments in general visual processing and nonface visual memory tasks either in conjunction with face perception deficits or as an isolated impairment. This finding may indicate an elevated risk for more general visuoperceptual deficits in families with prosopagnosic members.

Galactose uncovers face recognition and mental images in congenital prosopagnosia: the first case report.

A woman in her early 40s with congenital prosopagnosia and attention deficit hyperactivity disorder observed for the first time sudden and extensive improvement of her face recognition abilities, mental imagery, and sense of navigation after galactose intake. This effect of galactose on prosopagnosia has never been reported before. Even if this effect is restricted to a subform of congenital prosopagnosia, galactose might improve the condition of other prosopagnosics. Congenital prosopagnosia, the inability to recognize other people by their face, has extensive negative impact on everyday life. It has a high prevalence of about 2.5%. Monosaccharides are known to have a positive impact on cognitive performance. Here, we report the case of a prosopagnosic woman for whom the daily intake of 5 g of galactose resulted in a remarkable improvement of her lifelong face blindness, along with improved sense of orientation and more vivid mental imagery. All these improvements vanished after discontinuing galactose intake. The self-reported effects of galactose were wide-ranging and remarkably strong but could not be reproduced for 16 other prosopagnosics tested. Indications about heterogeneity within prosopagnosia have been reported; this could explain the difficulty to find similar effects in other prosopagnosics. Detailed analyses of the effects of galactose in prosopagnosia might give more insight into the effects of galactose on human cognition in general. Galactose is cheap and easy to obtain, therefore, a systematic test of its positive effects on other cases of congenital prosopagnosia may be warranted.

A computational model of dysfunctional facial encoding in congenital prosopagnosia.

Congenital prosopagnosia is a selective deficit in face identification that is present from birth. Previously, behavioral deficits in face recognition and differences in the neuroanatomical structure and functional activation of face processing areas have been documented mostly in separate studies. Here, we propose a neural network model of congenital prosopagnosia which relates behavioral and neuropsychological studies of prosopagnosia to theoretical models of information processing. In this study we trained a neural network with two different algorithms to represent face images. First, we introduced a predisposition towards a decreased network connectivity implemented as a temporal independent component analysis (ICA). This predisposition induced a featural representation of faces in terms of isolated face parts. Second, we trained the network for optimal information encoding using spatial ICA, which led to holistic representations of faces. The network model was then tested empirically in an experiment with ten prosopagnosic and twenty age-matched controls. Participants had to discriminate between faces that were changed either according to the prosopagnosic model of featural representation or to the control model of holistic representation. Compared to controls prosopagnosic participants were impaired only in discriminating holistic changes of faces but showed no impairment in detecting featural changes. In summary, the proposed model presents an empirically testable account of congenital prosopagnosia that links the critical features--a lack of holistic processing at the computational level and a sparse structural connectivity at the implementation level. More generally, our results point to structural differences in the network connectivity as the cause of the face processing deficit in congenital prosopagnosia.

Deficits in long-term recognition memory reveal dissociated subtypes in congenital prosopagnosia.

The study investigates long-term recognition memory in congenital prosopagnosia (CP), a lifelong impairment in face identification that is present from birth. Previous investigations of processing deficits in CP have mostly relied on short-term recognition tests to estimate the scope and severity of individual deficits. We firstly report on a controlled test of long-term (one year) recognition memory for faces and objects conducted with a large group of participants with CP. Long-term recognition memory is significantly impaired in eight CP participants (CPs). In all but one case, this deficit was selective to faces and didn't extend to intra-class recognition of object stimuli. In a test of famous face recognition, long-term recognition deficits were less pronounced, even after accounting for differences in media consumption between controls and CPs. Secondly, we combined test results on long-term and short-term recognition of faces and objects, and found a large heterogeneity in severity and scope of individual deficits. Analysis of the observed heterogeneity revealed a dissociation of CP into subtypes with a homogeneous phenotypical profile. Thirdly, we found that among CPs self-assessment of real-life difficulties, based on a standardized questionnaire, and experimentally assessed face recognition deficits are strongly correlated. Our results demonstrate that controlled tests of long-term recognition memory are needed to fully assess face recognition deficits in CP. Based on controlled and comprehensive experimental testing, CP can be dissociated into subtypes with a homogeneous phenotypical profile. The CP subtypes identified align with those found in prosopagnosia caused by cortical lesions; they can be interpreted with respect to a hierarchical neural system for face perception.

Spectrum of skeletal abnormalities in a complex malformation syndrome with "cutis tricolor" (Ruggieri-Happle syndrome).

BACKGROUND: The term cutis tricolor describes the combination of congenital hyper- and hypopigmented skin lesions in close proximity to each other in a background of normal complexion. This phenomenon has been reported: (i) as a purely cutaneous trait; (ii) as a part of a complex malformation syndrome (Ruggieri-Happle syndrome - RHS); (iii) as a distinct type [cutis tricolor parvimaculata]; (iv) in association with other (e.g. vascular) skin disturbances. OBJECTIVES: To delineate the spectrum of skeletal defects in cutis tricolor. METHODS: Retrospective and prospective analysis of skeletal surveys in 14 subjects (eight men; six women; aged 2-28 years) with cutis tricolor [4 purely cutaneous trait; 10 syndromic (RHS)]. RESULTS: Bone abnormalities were recorded in 71.4% (10/14) of patients [100% (10/10) of cases with (other-than-skeletal) extra-cutaneous manifestations vs. null (0/4) in cases with purely cutaneous traits] and included overall small skull (n = 6); prognathism (n = 6); 'J'-shaped pituitary fossa (n = 1); absence of atlas posterior arch (n = 3); frontal bossing (n = 6); scoliosis (n = 9) with kyphosis (n = 6) and/or lordosis (n = 6); vertebral (n = 9) and ribs (n = 4) defects. Negative ZFHX1B gene analyses excluded overlaps with Mowat-Wilson syndrome. CONCLUSIONS: Cutis tricolor may be a marker of underlying skeletal involvement particularly in subjects with a complex syndromic (RHS) phenotype.

Unexpected island effects at an extreme: reduced Y chromosome and mitochondrial DNA diversity in Nias.

The amount of genetic diversity in a population is determined by demographic and selection events in its history. Human populations which exhibit greatly reduced overall genetic diversity, presumably resulting from severe bottlenecks or founder events, are particularly interesting, not least because of their potential to serve as valuable resources for health studies. Here, we present an unexpected case, the human population of Nias Island in Indonesia, that exhibits severely reduced Y chromosome (non-recombining portion of the Y chromosome [NRY]) and to a lesser extent also reduced mitochondrial DNA (mtDNA) diversity as compared with most other populations from the Asia/Oceania region. Our genetic data, collected from more than 400 individuals from across the island, suggest a strong previously undetected bottleneck or founder event in the human population history of Nias, more pronounced for males than for females, followed by subsequent genetic isolation. Our findings are unexpected given the island's geographic proximity to the genetically highly diverse Southeast Asian world, as well as our previous knowledge about the human history of Nias. Furthermore, all NRY and virtually all mtDNA haplogroups observed in Nias can be attributed to the Austronesian expansion, in line with linguistic data, and in contrast with archaeological evidence for a pre-Austronesian occupation of Nias that, as we show here, left no significant genetic footprints in the contemporary population. Our work underlines the importance of human genetic diversity studies not only for a better understanding of human population history but also because of the potential relevance for genetic disease-mapping studies.

The early time course of compensatory face processing in congenital prosopagnosia.

BACKGROUND: Prosopagnosia is a selective deficit in facial identification which can be either acquired, (e.g., after brain damage), or present from birth (congenital). The face recognition deficit in prosopagnosia is characterized by worse accuracy, longer reaction times, more dispersed gaze behavior and a strong reliance on featural processing. METHODS/PRINCIPAL FINDINGS: We introduce a conceptual model of an apperceptive/associative type of congenital prosopagnosia where a deficit in holistic processing is compensated by a serial inspection of isolated, informative features. Based on the model proposed we investigated performance differences in different face and shoe identification tasks between a group of 16 participants with congenital prosopagnosia and a group of 36 age-matched controls. Given enough training and unlimited stimulus presentation prosopagnosics achieved normal face identification accuracy evincing longer reaction times. The latter increase was paralleled by an equally-sized increase in stimulus presentation times needed achieve an accuracy of 80%. When the inspection time of stimuli was limited (50 ms to 750 ms), prosopagnosics only showed worse accuracy but no difference in reaction time. Tested for the ability to generalize from frontal to rotated views, prosopagnosics performed worse than controls across all rotation angles but the magnitude of the deficit didn't change with increasing rotation. All group differences in accuracy, reaction or presentation times were selective to face stimuli and didn't extend to shoes. CONCLUSIONS/SIGNIFICANCE: Our study provides a characterization of congenital prosopagnosia in terms of early processing differences. More specifically, compensatory processing in congenital prosopagnosia requires an inspection of faces that is sufficiently long to allow for sequential focusing on informative features. This characterization of dysfunctional processing in prosopagnosia further emphasizes fast and holistic information encoding as two defining characteristics of normal face processing.

Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21.

Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation. In most cases, DS results from the presence of an extra copy of chromosome 21. DS has a complex phenotype, and a major goal of DS research is to identify genotype-phenotype correlations. Cases of partial trisomy 21 and other HSA21 rearrangements associated with DS features could identify genomic regions associated with specific phenotypes. We have developed a BAC array spanning HSA21q and used array comparative genome hybridization (aCGH) to enable high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving HSA21. We report the identification and mapping of 30 pathogenic chromosomal aberrations of HSA21 consisting of 19 partial trisomies and 11 partial monosomies for different segments of HSA21. The breakpoints have been mapped to within approximately 85 kb. The majority of the breakpoints (26 of 30) for the partial aneuploidies map within a 10-Mb region. Our data argue against a single DS critical region. We identify susceptibility regions for 25 phenotypes for DS and 27 regions for monosomy 21. However, most of these regions are still broad, and more cases are needed to narrow down the phenotypic maps to a reasonable number of candidate genomic elements per phenotype.