Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.

BACKGROUND: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines. RESULTS: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]≥250). There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)≥250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. CONCLUSIONS: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).

Novel NALCN variant linked to temporal lobe epilepsy.

The sodium leak channel (NALCN) gene encodes a sodium leak channel that plays an important role in the regulation of the resting membrane potential and the control of neuronal excitability. Mutations in the NALCN gene have been reported in patients with infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) and congenital contractures of the limbs and face with hypotonia and developmental delay (CLIFAHDD syndrome). We describe the case of a father with drug-resistant left temporo-orbitofrontal epilepsy and his son with mildly-symptomatic temporal epilepsy (only recurrent déjà vu auras) whose genetic panels identified a likely pathogenic deletion of exon 27 on the NALCN gene. Our study helps broaden the clinical spectrum of diseases associated with mutations in the NALCN gene.

XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.

XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.

Usage of Genetic Panels in an Adult Epilepsy Clinic.

BACKGROUND: There is limited data on the utility, yield, and cost efficiency of genetic testing in adults with epilepsy. We aimed to describe the yield and utility of genetic panels in our adult epilepsy clinic. METHODS: We performed a retrospective, cross-sectional study of all patients followed by an epileptologist at a Canadian tertiary care centre's epilepsy clinic between January 2016 and August 2021 for whom a genetic panel was ordered. A panel was generally ordered when the etiology was unknown or in the presence of a malformation of cortical development. We determined the yield of panel positivity and of confirmed genetic diagnoses. We also estimated the proportion of these diagnoses that were clinically actionable. RESULTS: In total, 164 panels were ordered in 164 patients. Most had refractory epilepsy (80%), and few had comorbid intellectual disability (10%) or a positive family history of epilepsy (11%). The yield of panel positivity was 11%. Panel results were uncertain 49% of the time and negative 40% of the time. Genetic diagnoses were confirmed in 7 (4.3%) patients. These genetic conditions involved the following genes: SCARB2, DEPDC5, PCDH19, LGI1, SCN1A, MT-TL1, and CHRNA7. Of the seven genetic diagnoses, 5 (71%) were evaluated to be clinically actionable. CONCLUSION: We report a lower diagnostic yield for genetic panels in adults with epilepsy than what has so far been reported. Although the field of the genetics of epilepsy is a fast-moving one and more data is required, our findings suggest that guidelines for genetic testing in adults are warranted.

Does the adenosine deaminase (ADA) gene confer risk of sleepwalking?

Sleepwalking is a common non-rapid eye movement (NREM) parasomnia and a significant cause of sleep-related injuries. While evidence suggest that the occurrence of this condition is partly determined by genetic factors, its pattern of inheritance remains unclear, and few molecular studies have been conducted. One promising candidate is the adenosine deaminase (ADA) gene. Adenosine and the ADA enzyme play an important role in the homeostatic regulation of NREM sleep. In a single sleepwalking family, genome-wide analysis identified a locus on chromosome 20, where ADA lies. In this study, we examined if variants in the ADA gene were associated with sleepwalking. In total, 251 sleepwalking patients were clinically assessed, and DNA samples were compared to those from 94 unaffected controls. Next-generation sequencing of the whole ADA gene was performed. Bio-informatic analysis enabled the identification of variants and assessed variants enrichment in our cohort compared to controls. We detected 25 different coding and non-coding variants, of which 22 were found among sleepwalkers. None were enriched in the sleepwalking population. However, many missense variants were predicted as likely pathogenic by at least two in silico prediction algorithms. This study involves the largest sleepwalking cohort in which the role of a susceptibility gene was investigated. Our results did not reveal an association between ADA gene and sleepwalking, thus ruling out the possibility of ADA as a major genetic factor for this condition. Future work is needed to identify susceptibility genes.

TDP-43 stabilizes G3BP1 mRNA: relevance to amyotrophic lateral sclerosis/frontotemporal dementia.

TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis. Defective stress granule assembly is associated with increased cellular vulnerability and death. Ras-GAP SH3-domain-binding protein 1 (G3BP1) is a critical stress granule assembly factor. Here, we define that TDP-43 stabilizes G3BP1 transcripts via direct binding of a highly conserved cis regulatory element within the 3' untranslated region. Moreover, we show in vitro and in vivo that nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels. Finally, we establish that G3BP1 transcripts are reduced in ALS/FTD patient neurons bearing TDP-43 cytoplasmic inclusions/nuclear depletion. Thus, our data indicate that, in ALS/FTD, there is a compromised stress granule response in disease-affected neurons due to impaired G3BP1 mRNA stability caused by TDP-43 nuclear depletion. These data implicate TDP-43 and G3BP1 loss of function as contributors to disease.

SHORT syndrome due to a novel de novo mutation in PRKCE (Protein Kinase Cɛ) impairing TORC2-dependent AKT activation.

SHORT syndrome is a rare, recognizable syndrome resulting from heterozygous mutations in PIK3R1 encoding a regulatory subunit of phosphoinositide-3-kinase (PI3K). The condition is characterized by short stature, intrauterine growth restriction, lipoatrophy and a facial gestalt involving a triangular face, deep set eyes, low hanging columella and small chin. PIK3R1 mutations in SHORT syndrome result in reduced signaling through the PI3K-AKT-mTOR pathway. We performed whole exome sequencing for an individual with clinical features of SHORT syndrome but negative for PIK3R1 mutation and her parents. A rare de novo variant in PRKCE was identified. The gene encodes PKCε and, as such, the AKT-mTOR pathway function was assessed using phospho-specific antibodies with patient lymphoblasts and following ectopic expression of the mutant in HEK293 cells. Kinase analysis showed that the variant resulted in a partial loss-of-function. Whilst interaction with PDK1 and the mTORC2 complex component SIN1 was preserved in the mutant PKCε, it bound to SIN1 with a higher affinity than wild-type PKCε and the dynamics of mTORC2-dependent priming of mutant PKCε was altered. Further, mutant PKCε caused impaired mTORC2-dependent pAKT-S473 following rapamycin treatment. Reduced pFOXO1-S256 and pS6-S240/244 levels were also observed in the patient LCLs. To date, mutations in PIK3R1 causing impaired PI3K-dependent AKT activation are the only known cause of SHORT syndrome. We identify a SHORT syndrome child with a novel partial loss-of-function defect in PKCε. This variant causes impaired AKT activation via compromised mTORC2 complex function.

Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy.

There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders. This group of conditions has been termed inherited GPI deficiencies (IGDs), a subgroup of congenital disorders of glycosylation; they present with variable phenotypes, often including seizures, hypotonia and intellectual disability. Here, we report two siblings with compound heterozygous variants in the gene phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) (NM_153681.2: c.74T > C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34). PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis. Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of other IGD phenotypes. Functional studies with patient cells showed reduced PIGP mRNA levels, and an associated reduction of GPI-anchored cell surface proteins, which was rescued by exogenous expression of wild-type PIGP. This work associates mutations in the PIGP gene with a novel autosomal recessive IGD, and expands our knowledge of the role of PIG genes in human development.

Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability.

Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent "leak" channels, important for the establishment and maintenance of resting membrane potentials upon which action potentials are generated, are not well established in human disease. UNC80 is a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. Loss-of-function mutations of NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF). We report four individuals from three unrelated families who have homozygous missense or compound heterozygous truncating mutations in UNC80 and persistent hypotonia, encephalopathy, growth failure, and severe intellectual disability. Compared to control cells, HEK293T cells transfected with an expression plasmid containing the c.5098C>T (p.Pro1700Ser) UNC80 mutation found in one individual showed markedly decreased NALCN channel currents. Our findings demonstrate the fundamental significance of UNC80 and basal ionic conductance to human health.

Identification of a Recognizable Progressive Skeletal Dysplasia Caused by RSPRY1 Mutations.

Skeletal dysplasias are highly variable Mendelian phenotypes. Molecular diagnosis of skeletal dysplasias is complicated by their extreme clinical and genetic heterogeneity. We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family, comprising progressive spondyloepimetaphyseal dysplasia, short stature, facial dysmorphism, short fourth metatarsals, and intellectual disability. Combined autozygome/exome analysis identified a homozygous frameshift mutation in RSPRY1 with resulting nonsense-mediated decay. Using a gene-centric "matchmaking" system, we were able to identify a Peruvian simplex case subject whose phenotype is strikingly similar to the original Saudi family and whose exome sequencing had revealed a likely pathogenic homozygous missense variant in the same gene. RSPRY1 encodes a hypothetical RING and SPRY domain-containing protein of unknown physiological function. However, we detect strong RSPRY1 protein localization in murine embryonic osteoblasts and periosteal cells during primary endochondral ossification, consistent with a role in bone development. This study highlights the role of gene-centric matchmaking tools to establish causal links to genes, especially for rare or previously undescribed clinical entities.

Recessive osteogenesis imperfecta caused by missense mutations in SPARC.

Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC (GenBank: NM_003118.3; c.497G>A [p.Arg166His] in individual 1; c.787G>A [p.Glu263Lys] in individual 2). Published modeling and site-directed mutagenesis studies had previously shown that the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I. The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2. The migration of collagen type I alpha chains produced by these fibroblasts was mildly delayed on SDS-PAGE gel, suggesting some overmodification of collagen during triple helical formation. Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals. Analysis of an iliac bone sample from individual 2 showed that trabecular bone was hypermineralized on the material level. In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans.

Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8.

Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.

Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency.

Short-chain enoyl-CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile-onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteristic abnormal biochemical findings are secondary to dysfunction of valine metabolism. We describe four patients from two consanguineous families (one Pakistani and one Irish Traveler), who presented in infancy with LS. Urine organic acid analysis by GC/MS showed increased levels of erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconate (3-MGC). Increased urine excretion of methacrylyl-CoA and acryloyl-CoA related metabolites analyzed by LC-MS/MS, were suggestive of SCEH deficiency; this was confirmed in patient fibroblasts. Both families were shown to harbor homozygous pathogenic variants in the ECHS1 gene; a c.476A > G (p.Gln159Arg) ECHS1variant in the Pakistani family and a c.538A > G, p.(Thr180Ala) ECHS1 variant in the Irish Traveler family. The c.538A > G, p.(Thr180Ala) ECHS1 variant was postulated to represent a Canadian founder mutation, but we present SNP genotyping data to support Irish ancestry of this variant with a haplotype common to the previously reported Canadian patients and our Irish Traveler family. The presence of detectable erythro-2,3-dihydroxy-2-methylbutyrate is a nonspecific marker on urine organic acid analysis but this finding, together with increased excretion of 3-MGC, elevated plasma lactate, and normal acylcarnitine profile in patients with a Leigh-like presentation should prompt consideration of a diagnosis of SCEH deficiency and genetic analysis of ECHS1. ECHS1 deficiency can be added to the list of conditions with 3-MGA.

Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion.

Congenital myopathies define a heterogeneous group of neuromuscular diseases with neonatal or childhood hypotonia and muscle weakness. The genetic cause is still unknown in many patients, precluding genetic counselling and better understanding of the physiopathology. To identify novel genetic causes of congenital myopathies, exome sequencing was performed in three consanguineous families. We identified two homozygous frameshift mutations and a homozygous nonsense mutation in the mitogen-activated protein triple kinase ZAK. In total, six affected patients carry these mutations. Reverse transcription polymerase chain reaction and transcriptome analyses suggested nonsense mRNA decay as a main impact of mutations. The patients demonstrated a generalized slowly progressive muscle weakness accompanied by decreased vital capacities. A combination of proximal contractures with distal joint hyperlaxity is a distinct feature in one family. The low endurance and compound muscle action potential amplitude were strongly ameliorated on treatment with anticholinesterase inhibitor in another patient. Common histopathological features encompassed fibre size variation, predominance of type 1 fibre and centralized nuclei. A peculiar subsarcolemmal accumulation of mitochondria pointing towards the centre of the fibre was a novel histological hallmark in one family. These findings will improve the molecular diagnosis of congenital myopathies and implicate the mitogen-activated protein kinase (MAPK) signalling as a novel pathway altered in these rare myopathies.

MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability.

Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.

Matchmaking facilitates the diagnosis of an autosomal-recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1) gene.

Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease-gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created "matching" platforms. We describe four individuals from three unrelated families "matched" by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1. A single homozygous mutation in TRIT1 associated with similar features had previously been reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease-causing gene and interprets the variants as "pathogenic." TRIT1 functions to modify mitochondrial tRNAs and is necessary for protein translation. We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder.

Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype.

Mitochondrial protein synthesis is initiated by formylated tRNA-methionine, which requires the activity of MTFMT, a methionyl-tRNA formyltransferase. Mutations in MTFMT have been associated with Leigh syndrome, early-onset mitochondrial leukoencephalopathy, microcephaly, ataxia, and cardiomyopathy. We identified compound heterozygous MTFMT mutations in a patient with a mild neurological phenotype and late-onset progressive visual impairment. MRI studies documented a progressive and selective involvement of the retrochiasmatic visual pathway. MTFMT was undetectable by immunoblot analysis of patient fibroblasts, resulting in specific defects in mitochondrial protein synthesis and assembly of the oxidative phosphorylation complexes. This report expands the clinical and MRI phenotypes associated with MTFMT mutations, illustrating the complexity of genotype-phenotype relationships in mitochondrial translation disorders.

Homozygous mutation in the eukaryotic translation initiation factor 2alpha phosphatase gene, PPP1R15B, is associated with severe microcephaly, short stature and intellectual disability.

Protein translation is an essential cellular process initiated by the association of a methionyl-tRNA with the translation initiation factor eIF2. The Met-tRNA/eIF2 complex then associates with the small ribosomal subunit, other translation factors and mRNA, which together comprise the translational initiation complex. This process is regulated by the phosphorylation status of the α subunit of eIF2 (eIF2α); phosphorylated eIF2α attenuates protein translation. Here, we report a consanguineous family with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings. Whole-exome sequencing identified a homozygous missense mutation, c.1972G>A; p.Arg658Cys, in protein phosphatase 1, regulatory subunit 15b (PPP1R15B), a protein which functions with the PPP1C phosphatase to maintain dephosphorylated eIF2α in unstressed cells. The p.R658C PPP1R15B mutation is located within the PPP1C binding site. We show that patient cells have greatly diminished levels of PPP1R15B-PPP1C interaction, which results in increased eIF2α phosphorylation and resistance to cellular stress. Finally, we find that patient cells have elevated levels of PPP1R15B mRNA and protein, suggesting activation of a compensatory program aimed at restoring cellular homeostasis which is ineffective due to PPP1R15B alteration. PPP1R15B now joins the expanding list of translation-associated proteins which when mutated cause rare genetic diseases.

Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with neuropathy.

Multiple symmetric lipomatosis (MSL) is a mitochondrial disorder with impaired brown fat metabolism that has been associated with MERRF mutations in some, but not all, patients. We studied a sibling pair and an unrelated indiviadual who presented with MSL and neuropathy to determine the genetic etiology of this disorder in patients who did not carry the MSL-associated MERRF mutation. Whole-exome sequencing was performed on the siblings, and a rare, shared homozygous mutation in MFN2 (c.2119C>T: p.R707W) was identified. The mutation was not present in their healthy siblings. In silico programs predict it to be pathogenic, and heterozygous carriers of the MFN2 p.R707W substitution are known to have Charcot-Marie-Tooth (CMT) disease. A third, unrelated patient with multiple symmetrical lipomatosis and neuropathy also harbored the same homozygous mutation and had been previously diagnosed with CMT. Functional studies in patient fibroblasts demonstrate that the p.R707W substitution impairs homotypic (MFN2-MFN2) protein interactions required for normal activity and renders mitochondria prone to perinuclear aggregation. These findings show that homozygous mutations at p.R707W in MFN2 are a novel cause of multiple symmetrical lipomatosis.

Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy.

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome sequencing, we identified biallelic mutations in LAMA1 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes.