Amish nemaline myopathy and dilated cardiomyopathy caused by a homozygous contiguous gene deletion of TNNT1 and TNNI3 in a Mennonite child

Amish nemaline myopathy (ANM) is a severe congenital form of NM, known to be fatal in early childhood due to pulmonary insufficiency. Homozygous mutation in TNNT1 was originally ascertained in an Older Amish community in 2000. To date, only five reports with six pathogenic variants in TNNT1 have been described in both Amish and non-Amish families. Here, we describe a 16-month old female from a small Mennonite community from Mexico, presenting with congenital hypotonia and dilated cardiomyopathy, with a novel homozygous deletion of 19q13.42 of about 11 kb in size, encompassing TNNT1 and TNNI3. Cardiomyopathy has not been observed in association with ANM in previous reports. Conversely, homozygous mutation in TNNI3 have been described with dilated cardiomyopathy. Our report underscores the consideration of contiguous gene deletion in children with ANM who present with congenital hypotonia and cardiomyopathy. The report also expands the known spectrum of non-Amish related ANM mutations to include homozygous multi-exonic TNNT1 deletion.     

The «Amish» NM_000256.3:c.3330+2T>G splice variant in MYBPC3 associated with hypertrophic cardiomyopathy is an ancient Swiss mutation

MYBPC3 is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM). Several loss-of-function founder variants have been reported in MYBPC3 from various geographic regions, altogether suggestive of a modest or absent effect of these variants on reproductive fitness. One of them, a MYBPC3 splice variant, NM_000256.3:c.3330+2T > G, was first described in homozygous state in newborns presenting with a severe, recessive form of HCM among the Amish population and was later associated with adult-onset dominant HCM in heterozygous carriers. We here report this splice variant in heterozygous state in eight unrelated Swiss families with HCM, making it the most prevalent cardiomyopathy variant in western Switzerland. This variant was identified in patients using targeted (n = 5) or full-genome sequencing (n = 3). Given the prevalence of this variant in the Old Order Amish, Mennonites and Swiss populations, and given that both Amish and Mennonites founders originated from the Bern Canton in Switzerland, the MYBPC3, NM_000256.3:c.3330+2T > G variant appears to be of Swiss origin. Neighboring regions that hosted the first Amish settlements (Alsace, South Germany) should be on the lookout for that variant. The existence of MYBPC3 founder variants in different populations suggests that individuals with early-onset clinical disease may be the tip of the iceberg of a much larger number of asymptomatic carriers. Alternatively, reproductive fitness could even be slightly increased in some variant carriers to compensate for the reduction of fitness in the more severely affected ones, but this remains to be investigated.     

AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range

BackgroundHereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases that present with weakness and stiffness in the lower limb muscles and lead to progressive neurological decline. Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to complex HSP. This study aimed to identify causative genetic variants in consanguineous families with HSP from Azerbaijan and Pakistan.MethodsWe performed a thorough clinical and neuroradiological characterization followed by exome sequencing in 7 patients from 3 unrelated families. Segregation analysis was subsequently performed by Sanger sequencing.ResultsWe describe 7 patients (4 males, 2–31 years of age) with developmental delay and spasticity.Similar to the previously reported cases with AP4B1-associated HSP, cases in the present report besides spasticity in the lower limbs had additional features including microcephaly, facial dysmorphism, infantile hypotonia, and epilepsy. The imaging findings included thin corpus callosum, white matter loss, and ventriculomegaly.ConclusionIn this study, we report 7 novel cases of HSP caused by bi-allelic variants in AP4B1 in Azerbaijani and Pakistani families. Our observations will help clinicians observe and compare common and unique clinical features of AP4B1-associated HSP patients, further improving our current understanding of HSP.     

ST6GAL1 polymorphisms influence susceptibility and progression of IgA nephropathy in a Chinese Han population

BackgroundST6GAL1 has been identified as a novel susceptibility gene for IgA nephropathy (IgAN) in a previous genome-wide association study. The present study is aimed at exploring whether the genetic polymorphisms of ST6GAL1 gene correlate with IgAN susceptibility, clinical phenotypes and progression in a Chinese Han population.MethodsTwenty-six single nucleotide polymorphisms (SNPs) of ST6GAL1 were genotyped in 1000 biopsy-proven IgAN patients and 1000 control subjects of Chinese Han population using Sequenom MassARRAY iPLEX. A logistic regression analysis with age and sex as covariates was performed to evaluate the effects of ST6GAL1 gene polymorphisms on IgAN susceptibility. Kaplan-Meier method and Cox proportional hazard models were applied to analyze the associations between genetic variants and renal survival.ResultsWe found that rs7634389 (OR = 1.24, 95 % CI = 1.02−1.50, p_dominant = 0.034) and rs6784233 (OR = 1.23, 95 % CI = 1.05−1.45, p_additive = 0.013; OR = 1.28, 95 % CI = 1.05−1.55, p_dominant = 0.014) were associated with susceptibility of IgAN. In addition, rs7634389 was correlated with hyperuricemia (OR = 1.27, p = 0.012) and segmental glomerulosclerosis (OR = 1.21, p = 0.047) in IgAN patients. Furthermore, rs7634389 was independently associated with renal survival after adjustments for multiple confounders (hazard ratio [HR] = 0.51, 95 % CI = 0.33−0.78, p = 0.002). Haplotype analysis for ST6GAL1 polymorphisms confirmed their associations with the susceptibility to IgAN.ConclusionsOur research suggested that ST6GAL1 gene polymorphisms were implicated in IgAN susceptibility and clinical outcome in a Chinese Han population.     

Recessive GM3 synthase deficiency: Natural history,biochemistry, and therapeutic frontier

GM3 synthase, encoded by ST3GAL5, initiates synthesis of all downstream cerebral gangliosides. Here, we present biochemical, functional, and natural history data from 50 individuals homozygous for a pathogenic ST3GAL5 c.862C>T founder allele (median age 8.1, range 0.7–30.5 years). GM3 and its derivatives were undetectable in plasma. Weight and head circumference were normal at birth and mean Apgar scores were 7.7 ± 2.0 (1 min) and 8.9 ± 0.5 (5 min). Somatic growth failure, progressive microcephaly, global developmental delay, visual inattentiveness, and dyskinetic movements developed within a few months of life. Infantile-onset epileptic encephalopathy was characterized by a slow, disorganized, high-voltage background, poor state transitions, absent posterior rhythm, and spike trains from multiple independent cortical foci; >90% of electrographic seizures were clinically silent. Hearing loss affected cochlea and central auditory pathways and 76% of children tested failed the newborn hearing screen. Development stagnated early in life; only 13 (26%) patients sat independently (median age 30 months), three (6%) learned to crawl, and none achieved reciprocal communication. Incessant irritability, often accompanied by insomnia, began during infancy and contributed to high parental stress. Despite catastrophic neurological dysfunction, neuroimaging showed only subtle or no destructive changes into late childhood and hospitalizations were surprisingly rare (0.2 per patient per year). Median survival was 23.5 years. Our observations corroborate findings from transgenic mice which indicate that gangliosides might have a limited role in embryonic neurodevelopment but become vital for postnatal brain growth and function. These results have critical implications for the design and implementation of ganglioside restitution therapies.     

PRRT2-related phenotypes in patients with a 16p11.2 deletion

We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals. The presence of BIE, PKD and PKD/IC was retrospectively evaluated using questionnaires and medical records. We included 33 patients with a 16p11.2 deletion: three (9%) had BIE, none had PKD or PKD/IC. Twelve patients had a PRRT2 sequence variant: BIE was present in four (p?=?0.069), PKD in six (p?<?0.001) and PKD/IC in two (p?=?0.067). Most patients with a deletion had undergone genetic testing because of developmental problems (87%), whereas all patients with a sequence variant were tested because of a movement disorder (55%) or epilepsy (45%). BIE, PKD and PKD/IC clearly showed incomplete penetrance in patients with 16p11.2 deletions, but were found in all and 95% of patients with a PRRT2 sequence variant in our study and a large literature cohort, respectively. Deletions and sequence variants have the same underlying loss-of-function disease mechanism. Thus, differences in ascertainment have led to overestimating the frequency of BIE, PKD and PKD/IC in patients with a PRRT2 sequence variant. This has important implications for counseling if genome-wide sequencing shows such variants in patients not presenting the PRRT2-related phenotypes.     

De novo SCN3A missense variant associated with self-limiting generalized epilepsy with fever sensitivity

ObjectiveAlthough the number of affected individuals is relatively low, pathogenic SCN3A variants have been reported in a range of phenotypes, from focal epilepsy to severe developmental and epileptic encephalopathy with polymicrogyria.MethodsCase report and inclusion of current literature.ResultsHere, we report a normally developed boy with self-limiting generalized epilepsy with fever sensitivity due to a likely pathogenic SCN3A variant. He had febrile seizures from the age of one year, which were successfully treated with valproate. After tapering off medication, he only had rare breakthrough seizures, always associated with fever. At the age of 12 he continues to develop normally and have normal cognition. Reviewing the literature, there appears to be a correlation between functional outcome and phenotype. Gain of function SCN3A variants are seen in individuals with a severe epilepsy, cognitive impairment and brain malformations, while loss of function variants are seen in individuals with epilepsy, varying degrees of cognitive impairment, including normal cognition, but no brain malformations.SignificanceThe genotype-phenotype correlations in SCN3A-related disorders presented here, will be important for families and clinicians alike, for diagnostic as well as possibly future treatment options.     

Rare pathogenic variants in WNK3 cause X-linked intellectual disability

PurposeWNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown.MethodWe ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).ResultsWe identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition.ConclusionPathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.     

Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia

PurposeNonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants.MethodsWe carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients.ResultsStatistically significant enrichment of rare (minor allele frequency < 1 × 10^–5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10^–5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants.ConclusionWe found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.     

Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort

PurposeAutosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES).MethodsAfter excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes.ResultsWe detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects.ConclusionWe report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.     

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

PurposeNeurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit.MethodsMost cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits.ResultsWe describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly.ConclusionWe significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.     

Exome sequencing in congenital ataxia identifies two new candidate genes and highlights a pathophysiological link between some congenital ataxias and early infantile epileptic encephalopathies

PurposeTo investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes.MethodsSingleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes.ResultsWe identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant.ConclusionSingleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).     

Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration

PurposeWith the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis.MethodsIRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing.ResultsAmong 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro.ConclusionNoncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.     

Phenotype of ST3GAL3 deficient patients: A case and review of the literature

ST3GAL3 deficiency is an extremely rare autosomal recessive disorder caused by pathogenic mutations in the ST3GAL3 gene. Epilepsy, motor development delay, severe intellectual disability, and behavioral disorders have been reported to be associated with ST3GAL3 deficiency. In the present study, ST3GAL3 deficiency was caused by a homozygous splice-site mutation (NM_174964.4: c.936+1delG) in ST3GAL3. The patient described in this study was clinically similar to previously reported cases; nevertheless, we were able to detect repetitive behavior, previously not reported manifestations.     

The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature

PurposeGermline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations.MethodsWe report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing), genome sequencing.ResultsTwo copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes.ConclusionGermline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.     

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

PurposePathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy.MethodsThrough an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy.ResultsSixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism.ConclusionNEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic–atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.     

Biallelic variants in HECT E3 paralogs,HECTD4 and UBE3C,encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome

PurposePathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified.MethodsChromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes.ResultsIn total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect.ConclusionHECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.     

Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders

PurposeMissense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability.MethodsBy international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro.ResultsIn accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well.ConclusionBy identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders.     

SCYL1 variants cause a syndrome with lowγ-glutamyl-transferase cholestasis,acute liver failure,and neurodegeneration (CALFAN)

PurposeBiallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure. The occurrence of SCYL1 deficiency among patients with previously undetermined infantile cholestasis or acute liver failure has not been studied; furthermore, little is known regarding the hepatic phenotype.MethodsWe aimed to identify patients with SCYL1 variants within an exome-sequencing study of individuals with infantile cholestasis or acute liver failure of unknown etiology. Deep clinical and biochemical phenotyping plus analysis of liver biopsies and functional studies on fibroblasts were performed.ResultsSeven patients from five families with biallelic SCYL1 variants were identified. The main clinical phenotype was recurrent low γ-glutamyl-transferase (GGT) cholestasis or acute liver failure with onset in infancy and a variable neurological phenotype of later onset (CALFAN syndrome). Liver crises were triggered by febrile infections and were transient, but fibrosis developed. Functional studies emphasize that SCYL1 deficiency is linked to impaired intracellular trafficking.ConclusionSCYL1 deficiency can cause recurrent low-GGT cholestatic liver dysfunction in conjunction with a variable neurological phenotype. Like NBAS deficiency, it is a member of the emerging group of congenital disorders of intracellular trafficking causing hepatopathy.