Mendeliome
Gene: MACF1 Green List (high evidence)Green List (high evidence)
Biallelic neurodevelopmental disorder GREEN:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense in the early NMD-escape region. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants. Almost all of the missense are rare in gnomad however one p.Leu1349Met has over 1000 hets and 2 homs.
Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant
Monoallelic neurodevelopmental disorder GREEN:
There is a currently well established AD association with Lissencephaly 9 with complex brainstem malformation (MIM#618325) shown to have a GOF mechanism. 2 recent papers PMID: 40925378 Dekker J 2025 and PMID: 41629993 Xi J 2026 have recently reported at least 6 de novo NMD variants in individuals with a nonspecific neurodevelopmental disorder, including developmental delay in all and epilepsy or macro/microcephaly in some. All variants are absent from gnomad. The pLI for this gene is 1 but there are quite a few NMD variants in gnomad with high het counts- however these cluster in exons 36-41 and exon 4 which are only coding in the MANE transcripts and not in other refseq transcripts or highly expressed transcripts in Gtex.
The overlapping phenotype of the mono and biallelic neurodevelopmental disorders may be due to hypomorphic variants causing the biallelic disease, or there may be a correlation to do with the different isoforms of this gene or the location of the variants within the protein. Still a bit of uncertainty around these phenotypes due to the non-specific and variable phenotypes and limited functional validation but enough reports to call them green at this stage
Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.Created: 7 May 2026, 4:37 p.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Congenital myasthenic syndrome, MONDO:0018940, MACF1-related; Neurodevelopmental disorder (MONDO:0700092), MACF1-related
Publications
Green List (high evidence)
PMIDs 37721175 and 30842214: 3 individuals reported with bi-allelic variants in this gene and a myasthenic phenotype, two congenital, one adult. Some functional data supports association.Created: 2 Jan 2026, 5:02 p.m.
Nine individuals (including a pair of twins) reported with de novo variants in this gene.
Sources: Expert listCreated: 24 Jan 2020, 5:05 p.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Lissencephaly 9 with complex brainstem malformation, MIM# 618325; Congenital myasthenic syndrome, MONDO:0018940, MACF1-related
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Phenotypes for gene: MACF1 were changed from Lissencephaly 9 with complex brainstem malformation, MIM# 618325; Congenital myasthenic syndrome, MONDO:0018940, MACF1-related to Neurodevelopmental disorder (MONDO:0700092), MACF1-related; Lissencephaly 9 with complex brainstem malformation, MIM# 618325; Congenital myasthenic syndrome, MONDO:0018940, MACF1-related
Publications for gene: MACF1 were set to 30471716; 37721175; 30842214
Phenotypes for gene: MACF1 were changed from Lissencephaly 9 with complex brainstem malformation, MIM# 618325 to Lissencephaly 9 with complex brainstem malformation, MIM# 618325; Congenital myasthenic syndrome, MONDO:0018940, MACF1-related
Publications for gene: MACF1 were set to 30471716
Mode of pathogenicity for gene: MACF1 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Mode of inheritance for gene: MACF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: macf1 has been classified as Green List (High Evidence).
Gene: macf1 has been classified as Green List (High Evidence).
gene: MACF1 was added gene: MACF1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: MACF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MACF1 were set to 30471716 Phenotypes for gene: MACF1 were set to Lissencephaly 9 with complex brainstem malformation, MIM# 618325 Mode of pathogenicity for gene: MACF1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: MACF1 was set to GREEN
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.