Comparison of clinical geneticist and computer visual attention in assessing genetic conditions.

Artificial intelligence (AI) for facial diagnostics is increasingly used in the genetics clinic to evaluate patients with potential genetic conditions. Current approaches focus on one type of AI called Deep Learning (DL). While DL- based facial diagnostic platforms have a high accuracy rate for many conditions, less is understood about how this technology assesses and classifies (categorizes) images, and how this compares to humans. To compare human and computer attention, we performed eye-tracking analyses of geneticist clinicians (n = 22) and non-clinicians (n = 22) who viewed images of people with 10 different genetic conditions, as well as images of unaffected individuals. We calculated the Intersection-over-Union (IoU) and Kullback-Leibler divergence (KL) to compare the visual attentions of the two participant groups, and then the clinician group against the saliency maps of our deep learning classifier. We found that human visual attention differs greatly from DL model's saliency results. Averaging over all the test images, IoU and KL metric for the successful (accurate) clinician visual attentions versus the saliency maps were 0.15 and 11.15, respectively. Individuals also tend to have a specific pattern of image inspection, and clinicians demonstrate different visual attention patterns than non-clinicians (IoU and KL of clinicians versus non-clinicians were 0.47 and 2.73, respectively). This study shows that humans (at different levels of expertise) and a computer vision model examine images differently. Understanding these differences can improve the design and use of AI tools, and lead to more meaningful interactions between clinicians and AI technologies.

Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.

ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

Next-generation phenotyping in Nigerian children with Cornelia de Lange syndrome.

Next-generation phenotyping (NGP) can be used to compute the similarity of dysmorphic patients to known syndromic diseases. So far, the technology has been evaluated in variant prioritization and classification, providing evidence for pathogenicity if the phenotype matched with other patients with a confirmed molecular diagnosis. In a Nigerian cohort of individuals with facial dysmorphism, we used the NGP tool GestaltMatcher to screen portraits prior to genetic testing and subjected individuals with high similarity scores to exome sequencing (ES). Here, we report on two individuals with global developmental delay, pulmonary artery stenosis, and genital and limb malformations for whom GestaltMatcher yielded Cornelia de Lange syndrome (CdLS) as the top hit. ES revealed a known pathogenic nonsense variant, NM_133433.4: c.598C>T; p.(Gln200*), as well as a novel frameshift variant c.7948dup; p.(Ile2650Asnfs*11) in NIPBL. Our results suggest that NGP can be used as a screening tool and thresholds could be defined for achieving high diagnostic yields in ES. Training the artificial intelligence (AI) with additional cases of the same ethnicity might further increase the positive predictive value of GestaltMatcher.

The IFITM5 Ser40Leu variant can manifest as prenatal Caffey disease.

We report on a female neonate with a clinico-radiological presentation in keeping with a lethal form of prenatal Caffey disease (PCH). She had antenatal and postnatal features of severely bowed long bones, small chest, diaphyseal hyperostosis and polyhydramnios and died shortly after birth. Initial testing excluded COL1A1-related PCH, as an OI gene panel, consisting of COL1A1, COL1A2, CRTAP, and P3H1 genes, was negative. Targeted sequencing using a gene panel was performed and a de novo heterozygous, likely pathogenic variant in IFITM5: c.119C > T(p.Ser40Leu) was identified, which was previously described to cause a severe form of progressively deforming osteogenesis imperfect (OI). To our knowledge, variants in IFITM5 have not been reported in infantile Caffey disease (ICH) or PCH. Given that the pathogenesis of PCH is largely unknown, we postulate that a subset of PCH may be associated with variants in IFITM5.

Perspectives on the future of dysmorphology.

The field of clinical genetics and genomics continues to evolve. In the past few decades, milestones like the initial sequencing of the human genome, dramatic changes in sequencing technologies, and the introduction of artificial intelligence, have upended the field and offered fascinating new insights. Though difficult to predict the precise paths the field will follow, rapid change may continue to be inevitable. Within genetics, the practice of dysmorphology, as defined by pioneering geneticist David W. Smith in the 1960s as "the study of, or general subject of abnormal development of tissue form" has also been affected by technological advances as well as more general trends in biomedicine. To address possibilities, potential, and perils regarding the future of dysmorphology, a group of clinical geneticists, representing different career stages, areas of focus, and geographic regions, have contributed to this piece by providing insights about how the practice of dysmorphology will develop over the next several decades.

Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.

Novel hemizygous loss-of-function variant in NONO identified in a South African boy.

Hemizygous loss-of-function variants in the non-POU domain-containing, octamer-binding gene, NONO, cause X-linked mental retardation syndrome 34 (MRXS34). Here, we describe the 12th patient in the literature with this rare syndrome, the first affected male from sub-Saharan Africa. This South African patient presented with dysmorphic features, congenital cardiac abnormalities (Ebstein's anomaly, left ventricular non-compaction, and a VSD), and developmental delay. He was enrolled in our "Undiagnosed Disease Programme." Exome sequencing identified a novel hemizygous 14bp deletion in NONO, which he inherited from his unaffected, healthy mother. His features overlap with the previous patients described, lending more support to the assertion that MRXS34 is a recognizable, albeit rare, syndrome. The cardiac anomalies are particularly distinctive, which combined with a variety of other associated features, should prompt the inclusion of NONO-associated MRXS34 in the differential diagnosis.

Undiagnosed disease program in South Africa: Results from first 100 exomes.

The Undiagnosed Disease Program in South Africa (UDP) sought to prospectively evaluate the clinical utility of exome sequencing (ES) in a phenotypically diverse, multi-ethnic cohort of South African patients with suspected rare genetic disorders. ES was undertaken in 100 sequential patients (93 singletons, 3 duos, and 4 trios) recruited to the UDP at Stellenbosch University. The data were analyzed through two separate bioinformatics pipelines (EVIDENCE from 3 billion and our in-house pipeline). A definitive diagnosis could be reached in 51% (51/100) patients, with 46% (46/100) patients having either pathogenic or likely pathogenic single-nucleotide variants/indels (SNVs/indels), and 5 patients with likely-pathogenic copy number variants (CNVs) (5/100). The CNVs were subsequently confirmed on microarray or MLPA analysis. Detailed phenotyping and HPO terms enabled analysis and variant identification. Twenty-five novel variants in 22 genes are reported here. We provide data from the first year of this UDP and show that even amongst mainly singletons from an understudied, diverse African population, ES is a valuable diagnostic tool, especially if it includes CNV analysis. The remaining undiagnosed patients present a unique opportunity for further research and novel gene discovery.

Genomic basis of syndromic short stature in an Algerian patient cohort.

Short stature is one of the most common reasons for a referral to the pediatric endocrinology clinic. Thousands of patients with short stature are assessed annually at the Department of Endocrine and Metabolic Diseases (DEMD) at Bab el Oued University Hospital in Algiers, Algeria. However, diagnostic rates in patients with syndromic short stature are not optimal due to the unavailability of next generation sequencing (NGS) technology. Here, we enrolled 10 Algerian patients with syndromic short stature in a pilot study to test the impact of genetic and genomic approaches in the DEMD. Using a combination of two different NGS modalities, namely exome sequencing and the Mendeliome (TruSight™ One sequencing panel) along with single gene testing, we were able to establish a confirmed molecular diagnosis in 7/10 patients (70%) and to identify strong likely disease-causing variants in a further two patients. Novel variants in NPR2 and VPS13B were identified. Using copy number variation analysis on the exome data, we also identified a de novo deletion of the short arm of chromosome X. These definitive diagnoses have made a substantial impact on patient treatment, management and genetic counseling. Genomic testing has the ability to transform clinical practice, and is an essential diagnostic tool in any tertiary pediatric clinic, particularly in resource limited settings.

High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.

Altered FGF signalling in congenital craniofacial and skeletal disorders.

The fibroblast growth factor (FGF) signalling pathway has been the focus of intense genetic and functional research for several decades. The emerging data implicate FGF signalling in diverse regulatory processes, both in the developing embryo as well as in the adult organism. Alterations in this tightly regulated pathway can lead to a number of pathological conditions, ranging from well-recognized congenital disorders to cancer. In order to mediate their cellular processes, FGFs signal through a subfamily of tyrosine kinase receptors, called FGF receptors (FGFRs). In humans, four FGFRs are described, and, to date, mutations in FGFR1, FGFR2, and FGFR3 have been shown to underlie human developmental disorders. FGFs/FGFRs are known to be key players in both endochondral and intramembranous bone development. In this review, we focus on the major developmental craniofacial and skeletal disorders which result from altered FGF signalling.

Uncommon IFITM5 mutation associated with severe skeletal deformity in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is the most common skeletal dysplasia, which predisposes to recurrent fractures and bone deformity and presents with wide clinical variability. More than 80% of OI cases are related to dominantly inherited mutations in COL1A1 or COL1A2. The rest of the cases, however, involve many other noncollagen genes, all of which are autosomal-recessively inherited, except for IFITM5 and WNT1, which are also associated with autosomal dominant OI. Since 2012, a single recurrent heterozygous mutation in IFITM5 (c.-14C>T) has been shown to underlie OI type V. Although this is the most common OI-causing mutation in IFITM5, a second, less common mutation in IFITM5, c.119C>T (p.Ser40Leu), has been identified, which is not associated with the OI type V phenotype. In this report, we describe the clinical and radiological features of a further patient with this uncommon mutation in IFITM5 (c.119C>T, p.Ser40Leu). The patient presented with prenatal signs of severe OI and developed extreme short stature with short and bowed limbs, relative macrocephaly, scoliosis, vertebral compression, and a hypoplastic thorax. He had global developmental delay, recurrent respiratory problems, and required special family care and multidisciplinary treatment. To date, all patients with the uncommon c.119C>T mutation have presented with severe OI, rather than OI type V. Thus, this report further strengthens the case for a genotype-phenotype correlation for IFITM5-related OI.

Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome.

Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs(∗)6), in CKAP2L, encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome.

Smith-Kingsmore syndrome: A third family with the MTOR mutation c.5395G>A p.(Glu1799Lys) and evidence for paternal gonadal mosaicism.

Heterozygous germline mutations in MTOR have been shown to underlie Smith-Kingsmore syndrome, a rare autosomal dominant syndrome characterized by macrocephaly, developmental delay, and dysmorphic facial features. Recently, two unrelated families with the MTOR mutation, c.5395G>A p.(Glu1799Lys), were reported. Here, we describe siblings from a non-consanguineous German family in whom we identified the same heterozygous missense mutation in MTOR. Remarkably, in all reported families with Smith-Kingsmore syndrome and the MTOR c.5395G>A mutation, including the family described herein, healthy parents of recurrently affected children do not have detectable levels of the mutation in tested tissues, lending credence to gonadal mosaicism as the underlying mechanism. Furthermore, the glutamic acid at position 1799 was shown to present a recurrent somatic mutation site in several cancers, including colon cancer, pointing to a somatic mutational hotspot in MTOR. Importantly, we highlight the occurrence of multiple intestinal polyps in the older sibling. Further patients are required to establish definitively whether polyp formation forms part of the SKS clinical spectrum. © 2016 Wiley Periodicals, Inc.

Confirmation of CAGSSS syndrome as a distinct entity in a Danish patient with a novel homozygous mutation in IARS2.

Since the original description of the IARS2-related cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, skeletal dysplasia syndrome (CAGSSS; OMIM 616007) in an extended consanguineous family of French-Canadian descent, no further patients have been reported. IARS2 (OMIM 612801) encodes the mitochondrial isoleucine-tRNA synthetase which belongs to the class-I aminoacyl-tRNA synthetase family, and has been implicated in CAGSSS and a form of Leigh syndrome. Here, we report on a female Danish patient with a novel homozygous IARS2 mutation, p.Gly874Arg, who presented at birth with bilateral hip dislocation and short stature. At 3 months, additional dysmorphic features were noted and at 18 months her radiographic skeletal abnormalities were suggestive of an underlying spondyloepimetaphyseal dysplasia (SEMD). Retrospective analysis of the neonatal radiographs confirmed that the skeletal changes were present at birth. It was only with time that several of the other manifestations of the CAGSSS emerged, namely, cataracts, peripheral neuropathy, and hearing loss. Growth hormone deficiency has not (yet) manifested. We present her clinical features and particularly highlight her skeletal findings, which confirm the presence of a primary SEMD skeletal dysplasia in a growing list of mitochondrial-related disorders including CAGSSS, CODAS, EVEN-PLUS, and X-linked SEMD-MR syndromes.

Novel IFT122 mutations in three Argentinian patients with cranioectodermal dysplasia: Expanding the mutational spectrum.

Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is an autosomal recessive ciliary chondrodysplasia characterized by a recognizable craniofacial gestalt, skeletal abnormalities, and ectodermal features. To date, four genes have been shown to underlie the syndrome, namely, IFT122 (WDR10), WDR35 (IFT121), IFT43 (C14orf179), and WDR19 (IFT144). Clinical characterization of a larger cohort of patients with CED has been undertaken previously. Nevertheless, there are too few molecularly confirmed patients reported in the literature to determine precise genotype-phenotype correlations. To date, biallelic IFT122 mutations have been described in only five families. We therefore studied three unrelated Argentinian patients with typical features of CED using a 4813 next-generation sequencing (NGS) gene panel, which we call the "Mendeliome." The three patients had different, novel, compound heterozygous mutations in IFT122. Consequently, we compared these three patients to those previously described with IFT122 mutations. Thus, our report serves to add 6 novel mutations to the IFT122 mutation spectrum and to contribute to the IFT122-related clinical characterization.

Utility of next generation sequencing in paediatric neurological disorders: experience from South Africa.

Next generation sequencing (NGS)-based tests have become routine first-line investigative modalities in paediatric neurology clinics in many high-income countries (HICs). Studies from these countries show that these tests are both cost-effective and reliable in diagnosing many complex childhood neurological diseases. However, NGS-based testing in low-and middle-income countries (LMICs) is limited due to affordability constraints. The primary objective of this study was to evaluate the diagnostic yield and impact of targeted gene panel sequencing in a selected paediatric cohort attending a tertiary paediatric neurology clinic in the Western Cape Province of South Africa. This retrospective study included 124 consecutive paediatric patients with neurological disease, aged 6 weeks to 17 years, referred for NGS-based multi-gene panel testing over a 41-month period. Twenty-four different disease group-specific panels were utilized. A caregiver experience questionnaire was administered when a pathogenic variant was identified. The overall study diagnostic yield (DY) was 45% (56/124 patients). The diagnostic yield in this study is similar to previously reported paediatric cohorts in HICs. The high yields for neuromuscular disorders (52%) and early epileptic encephalopathies (41%) suggest that NGS-based panels may be more cost-effective as first-line testing in well-defined phenotypes. The latter finding argues for early inclusion of all children with developmental epileptic encephalopathies (DEE), as early diagnosis leads to better treatment and avoidance of unnecessary investigations.

GestaltMatcher Database - A global reference for the facial phenotypic variability of rare human diseases.

Dysmorphologists sometimes encounter challenges in recognizing disorders due to phenotypic variability influenced by factors such as age and ethnicity. Moreover, the performance of Next Generation Phenotyping Tools such as GestaltMatcher is dependent on the diversity of the training set. Therefore, we developed GestaltMatcher Database (GMDB) - a global reference for the phenotypic variability of rare diseases that complies with the FAIR-principles. We curated dysmorphic patient images and metadata from 2,224 publications, transforming GMDB into an online dynamic case report journal. To encourage clinicians worldwide to contribute, each case can receive a Digital Object Identifier (DOI), making it a citable micro-publication. This resulted in a collection of 2,312 unpublished images, partly with longitudinal data. We have compiled a collection of 10,189 frontal images from 7,695 patients representing 683 disorders. The web interface enables gene- and phenotype-centered queries for registered users (https://db.gestaltmatcher.org/). Despite the predominant European ancestry of most patients (59%), our global collaborations have facilitated the inclusion of data from frequently underrepresented ethnicities, with 17% Asian, 4% African, and 6% with other ethnic backgrounds. The analysis has revealed a significant enhancement in GestaltMatcher performance across all ethnic groups, incorporating non-European ethnicities, showcasing a remarkable increase in Top-1-Accuracy by 31.56% and Top-5-Accuracy by 12.64%. Importantly, this improvement was achieved without altering the performance metrics for European patients. GMDB addresses dysmorphology challenges by representing phenotypic variability and including underrepresented groups, enhancing global diagnostic rates and serving as a vital clinician reference database.

GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases.

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.

B3GALT6-linkeropathy: Three illustrative patients spanning the disease spectrum.

The linkeropathies are a group of rare disorders, characterized by overlapping clinical features involving the skeletal and connective tissues. Each "linker" gene encodes an enzyme responsible for the addition of glycosaminoglycan chains to proteoglycans via a common tertrasaccharine linker region. The original descriptions of the autosomal recessive B3GALT6-related disorder showed that the associated clinical features are pleiotropic, spanning the skeletal dysplasia (Spondyloepimetaphyseal dysplasia with joint laxity) (SEMD-JL1) and connective tissue disorder (Ehlers-Danlos syndrome) (EDS spondylodysplastic Type 2) spectrum. Here, we describe three patients with biallelic B3GALT6 variants: each had different clinical presentations, and the two older patients initially received alternative clinical diagnoses (Larsen syndrome and Osteogenesis imperfecta, respectively). We describe the clinico-radiological features of these patients to highlight the spectrum of disease associated with the B3GALT6-linkeropathy.