Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis

Mendelian MONDO:0010516 Pathograph 20 Show in embeddings browser X-linked Mendelian disease

This is the disease that was left over when a contiguous-gene deletion syndrome was taken apart. AMME - Alport syndrome, intellectual disability, midface hypoplasia and elliptocytosis - was described in 1998 as an Xq22.3 microdeletion spanning COL4A5 and its neighbours. COL4A5 explained the Alport syndrome and nothing else, so the remaining features had to belong to a neighbouring gene. AMMECR1 was cloned out of the deleted interval the following year and named for the syndrome, with no known function. Two decades later the assignment was confirmed from the other direction: point mutations and microdeletions that hit AMMECR1 but spare COL4A5 reproduce the non-renal AMME features and not Alport syndrome. What is left is this entity - midface hypoplasia, sensorineural hearing loss, elliptocytosis and nephrocalcinosis, usually with short stature and developmental delay, and in the larger series with cardiac and skeletal abnormalities as well. The mechanism is genuinely open, and the entry says so rather than dressing it up. AMMECR1 is a nuclear protein with a nucleic-acid-binding RAGNYA fold that dimerizes with its paralog AMMECR1L; it is coexpressed with cell-cycle genes, several of which have their own growth and bone phenotypes, and its authors put this no more strongly than "potentially involved in cell cycle control". The one functional handle on a patient allele is localisation: the p.G177D missense protein distributes abnormally within the nucleus. How any of that produces midface hypoplasia or renal calcification is not known. One negative result deserves to survive from the original 1998 report, because it rules out the obvious explanation for the blood finding. The elliptocytosis here is not hereditary elliptocytosis: red cell membrane proteins were normal, and membrane stability and rigidity were normal on ektacytometry. Whatever deforms the red cells, it is not the spectrin-actin membrane skeleton defect that carries that name in haematology.

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Inheritance
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Pathophys.
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Phenotypes
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Gaps
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Pathograph
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Genes
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Medical Actions
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Models
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Inheritance

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X-linked recessive HP:0001419
Affected individuals are males hemizygous for an AMMECR1 point mutation or microdeletion, typically inherited from an unaffected or mildly affected mother; de novo variants are also reported.
X-linked recessive inheritance
Show evidence (2 references)
PMID:28089922 SUPPORT Human Clinical
"In this study, we report a family with X-linked recessive syndrome caused by mutated AMMECR1 and characterized by elliptocytosis with or without anemia, midface hypoplasia, proportionate short stature and hearing loss."
States the inheritance pattern and the core phenotype in one sentence.
PMID:29193635 SUPPORT Human Clinical
"We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants."
The allelic and inheritance spectrum across five individuals, including maternal transmission, a de novo variant, and the X-autosome translocation case.
X-linked, with a partial phenotype in female carriers HP:0001417
Carrier females are not uniformly unaffected. Three female relatives of a male fetus carrying an intragenic AMMECR1 deletion all reported hearing loss, with mild to moderate sensorineural loss on audiometry, and one had a soft cleft palate and hip dysplasia. This is recorded as a separate inheritance entry rather than folded into the recessive one, because it changes what a carrier should be told.
X-linked inheritance
Show evidence (2 references)
PMID:35084080 SUPPORT Human Clinical
"All three women reported hearing loss and one was born with a soft cleft palate and hip dysplasia."
The carrier findings themselves.
PMID:35084080 SUPPORT Human Clinical
"we suggest that female carriers may display a partial phenotype in this X-linked condition"
The authors' own conclusion, stated as a suggestion rather than an established rule, which is how it is recorded here.
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Discussions and Knowledge Gaps

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What does AMMECR1 actually do in the nucleus, and by what route does losing it produce midface hypoplasia, hearing loss, nephrocalcinosis and elliptocytosis?
KNOWLEDGE GAP mhen_mechanism_entirely_unknown
Attached to
pathophysiology#Disturbed Cell-Cycle-Associated Program in Developing Tissues
Twenty-seven years after the syndrome was described and twenty-six after the gene was cloned, the function of AMMECR1 is stated in the literature as unknown or, at its strongest, as "potentially involved in cell cycle control" on the basis of coexpression. There is no assay of AMMECR1 activity, no cell-cycle measurement in patient material, and no proposed route from the gene to any one of the four features in the disease name. This is not a gap in one branch of an otherwise worked-out mechanism - it is the whole mechanism, and the entry's causal edges are typed with unknown intermediates for that reason. The tractable next steps are the obvious ones: a conditional mouse or a patient-derived cell model with an actual readout, and a molecular function for the RAGNYA fold beyond the sequence prediction.
Why do the red cells become elliptical when the membrane skeleton is intact?
KNOWLEDGE GAP mhen_elliptocytosis_not_membrane_defect
Attached to
pathophysiology#Elliptocytosis Without a Membrane Skeleton Defect
Hereditary elliptocytosis is a disease of the spectrin-actin membrane skeleton, and the obvious hypothesis for an inherited elliptocytosis is that the same machinery is affected. That hypothesis was tested in the original AMME family and failed: red cell membrane proteins were normal and ektacytometry showed normal membrane stability and rigidity. So the morphology is produced some other way - plausibly during erythropoiesis rather than in the mature cell, given a nuclear protein with a proposed cell-cycle role - and nobody has looked. A negative result this clean, left unfollowed for a quarter century, is unusually good value for a small experiment.
How often, and how severely, are female AMMECR1 carriers affected?
KNOWLEDGE GAP mhen_female_carrier_phenotype
Attached to
inheritance#X-linked, with a partial phenotype in female carriers
All three carrier females in the one report that examined them had hearing loss, and one had a cleft palate and hip dysplasia - and separately, one of the five patients in the loss-of-function series is a girl, affected because a balanced X-autosome translocation inactivated her normal X. So the "recessive" label is doing less work than it appears to. Three women is not a denominator, no other report audiometrically examines carriers, and the counselling consequence is direct: a carrier mother currently gets a recurrence risk without any statement of her own risk. Resolving it needs systematic audiometry in obligate carriers across the reported families, with X-inactivation studies alongside.
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Pathophysiology

4
AMMECR1 Loss of Function
The initiating lesion. Reported alleles span the range: microdeletions removing AMMECR1 alone or with its immediate neighbours TMEM164 and SNORD96B, nonsense variants, an X-autosome translocation with skewed inactivation of the normal X, and missense changes. AMMECR1 sits in the Xq22.3 interval deleted in AMME, and the disease-defining observation is that variants hitting AMMECR1 while sparing COL4A5 reproduce the non-renal AMME features without Alport syndrome. The gene encodes a 35.5 kDa protein from six exons with a ubiquitous transcript, conserved from yeast and nematode upward. When it was cloned, its function was unknown; a conserved six-amino-acid domain in exon 2 was noted with function unknown then, and it remains substantially unknown now.
AMMECR1 hgnc:467 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AMMECR1 (hgnc:467). hgnc:467 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Hemizygous in affected males - microdeletion, nonsense or missense. The functional impact is recorded as loss of function because the microdeletion and nonsense alleles are unambiguous and produce the same phenotype as the missense ones; whether every missense allele acts by simple loss of function is not established.
Downstream
Loss of Nuclear AMMECR1 Function Deleting the gene removes the protein outright; the studied missense allele leaves the protein present but abnormally distributed within the nucleus. Both routes converge on the absence of normal nuclear AMMECR1 activity.
Show evidence (3 references)
PMID:27811305 SUPPORT Human Clinical
"In the affected half-brothers, we identified a hemizygous novel non-synonymous variant of unknown significance in AMMECR1 (c.G530A; p.G177D), a gene residing in the AMME disease locus."
The first point mutation in the gene, in the family that separated AMMECR1's contribution from the rest of the AMME deletion.
PMID:30737907 SUPPORT Human Clinical
"These original cases further confirm that most specific AMME features are ascribed to AMMECR1 haploinsufficiency."
Independent confirmation from the deletion side that this gene, not its neighbours, carries the non-renal phenotype.
PMID:10049589 SUPPORT Other
"AMMECR1 is composed of six exons, shows a ubiquitous 6.5-kb transcript, and codes for a protein with a molecular mass of 35.5 kDa."
The gene's basic architecture, from the report that cloned it out of the AMME deletion interval. Graded OTHER because this is molecular cloning and sequence analysis rather than any of the study types the other values name.
Loss of Nuclear AMMECR1 Function
AMMECR1 and its paralog AMMECR1L dimerize and localize to the nucleus, which their nucleic-acid-binding RAGNYA folds would predict. The one patient allele examined functionally, p.G177D, is not absent from the nucleus but distributed abnormally within it - and the second reported missense allele is described the same way, as altered intranuclear distribution with reduced expression. What the protein does there is unresolved. The strongest statement its investigators make is that it is potentially involved in cell cycle control, inferred from coexpression rather than from an assay of AMMECR1 itself. This node therefore records a demonstrated molecular abnormality with an undetermined downstream function, which is the honest shape of the evidence.
nucleic acid binding, predicted from the RAGNYA fold GO:0003676 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves nucleic acid binding, predicted from the RAGNYA fold, annotated with nucleic acid binding (GO:0003676), qualified as loss of function. GO:0003676 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
nucleus GO:0005634 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nucleus (GO:0005634). GO:0005634 is a cellular component from the Gene Ontology.
Downstream
Disturbed Cell-Cycle-Associated Program in Developing Tissues The proposed consequence, and the weakest link in this chain. It rests on AMMECR1's coexpression with cell-cycle genes and on the zebrafish knockdown phenotype, not on any measurement of cell-cycle progression in patient cells.
Elliptocytosis Without a Membrane Skeleton Defect Drawn separately from the developmental branch because the original family's red cells were shown *not* to have the membrane defect that ordinarily causes elliptocytosis, so this is not a downstream consequence of any established mechanism. The edge records that the blood phenotype tracks AMMECR1 loss; its intermediates are unknown.
Show evidence (4 references)
PMID:29193635 SUPPORT INDIRECT Computational
"AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds."
The structural and localisation account of the normal protein. Graded COMPUTATIONAL because the nucleic-acid-binding function is a fold-based prediction, and INDIRECT because it describes the wild-type protein rather than a patient allele.
PMID:27811305 SUPPORT DIRECT In Vitro
"Transfected cell lines with the p.G177D mutation showed aberrant nuclear localisation patterns when compared with the wild type."
The only direct functional demonstration for a patient allele: the mutant protein mislocalises within the nucleus in transfected cells.
PMID:42386221 SUPPORT INDIRECT Human Clinical
"Comparative review of the literature highlights that while previously reported missense variants in AMMECR1 demonstrated altered intranuclear protein distribution and reduced expression in functional assays, clinical evidence supporting pathogenicity of non-truncating variants remains limited."
Confirms the intranuclear-distribution finding generalises across the reported missense alleles, and carries the authors' caveat about how thin the clinical evidence for non-truncating variants still is.
+ 1 more reference
Disturbed Cell-Cycle-Associated Program in Developing Tissues
Mechanism confidence: Hypothetical
The proposed bridge between a nuclear protein of unknown function and a multisystem developmental phenotype. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which already have growth and bone phenotypes of their own, and knocking down the zebrafish orthologue produces features reminiscent of the patients'. That is the entire basis; no cell-cycle measurement has been made in patient material, and the proposal is stated by its authors as a possibility. Recorded as a node anyway, because the alternative is a graph in which a gene deletion connects directly to seven unrelated clinical findings with nothing in between, which would misrepresent the literature in the opposite direction.
cell cycle control, proposed rather than demonstrated GO:0007049 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cell cycle control, proposed rather than demonstrated, annotated with cell cycle (GO:0007049). GO:0007049 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Animal models
Zebrafish ammecr1 morphant Zebrafish partially recapitulates Establishes that the gene is required for normal development in a vertebrate, which is the main thing this node needs and nearly the only thing the model supplies.
Downstream
Midface Hypoplasia The facial phenotype that named the syndrome. No mechanism connecting AMMECR1 to midfacial growth has been proposed in any source read here.
Sensorineural Hearing Impairment The one phenotype with a tissue-level foothold: AMMECR1 protein is expressed in the human fetal cochlea, so the gene is present where the deficit appears. Expression is not mechanism, and nothing further is claimed.
Short Stature Proportionate short stature is one of the most consistent features across reports, and the growth phenotype is what led to the cell-cycle coexpression hypothesis in the first place.
Developmental Delay and Intellectual Disability The "mental retardation" of the original AMME acronym, now attributed to AMMECR1 rather than to COL4A5 or the wider deletion.
Abnormal Heart Morphology Cardiac abnormalities appear in the five-individual loss-of-function series and are not reported in the earlier families, which is why they are curated as part of the spectrum rather than as a core feature.
Cleft Palate Midline palatal defects - a submucous cleft with bifid uvula in the first point-mutation family, a soft cleft palate in a female carrier - alongside the midface hypoplasia, which is what makes the facial phenotype a midline developmental one rather than isolated retrusion.
Congenital Hip Dysplasia Part of the skeletal component, reported both in affected males and in a carrier female.
Nephrocalcinosis The renal finding that is *not* Alport syndrome. It was the presenting problem in the first point-mutation family and recurs in the most recent missense case, but its investigators put the attribution no more strongly than that AMMECR1 may play a role in it. This edge is kept alongside the hypercalciuria route below rather than replaced by it, because the second half-brother's nephrocalcinosis has no reported hypercalciuria at all. Whatever the calcium-handling route explains, it does not explain every reported case.
Hypercalciuria Excessive urinary calcium excretion with a normal plasma calcium - so a renal tubular handling problem rather than a systemic hypercalcaemia. It is the only candidate intermediate any source offers for the renal phenotype, and it is why the first-report authors screened a panel of idiopathic-hypercalciuria genes before settling on AMMECR1.
Infantile Hypotonia Hypotonia from shortly after birth in one of the two point-mutation half-brothers, listed by the first-report authors among the features AMMECR1 loss contributes to. Explicitly absent in his half-brother, who met his motor milestones - so this edge describes a variably expressed consequence, not a constant one.
Show evidence (3 references)
PMID:29193635 SUPPORT INDIRECT Computational
"AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations."
The coexpression analysis that generated the hypothesis. COMPUTATIONAL and INDIRECT: it is a transcriptomic association, and the inference to cell-cycle involvement is one step beyond what it measures.
PMID:29193635 SUPPORT INDIRECT Model Organism
"Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features."
The animal evidence that the gene is required for normal development. "Reminiscent" is the authors' word and is not upgraded here.
PMID:29193635 SUPPORT Human Clinical
"Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis."
The authors' summary claim, at the strength they state it - "potentially involved" - which is why this node's `mechanism_confidence` is HYPOTHETICAL.
Elliptocytosis Without a Membrane Skeleton Defect
Mechanism confidence: Hypothetical
Elliptical red cells on the blood film, sometimes with anaemia. The important thing about this finding is what it is not: in the original AMME family the elliptocytosis was not accompanied by any detectable abnormality of red cell membrane proteins, and membrane stability and rigidity were normal on ektacytometry - the assay that is abnormal in hereditary elliptocytosis. So the shared name with hereditary elliptocytosis is a morphological coincidence, not a shared mechanism, and no mechanism has since been proposed.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
Downstream
Elliptocytosis The morphological finding itself, as seen on the peripheral blood smear.
Show evidence (2 references)
PMID:9598718 SUPPORT Human Clinical
"The elliptocytosis was not associated with any detectable abnormalities in red cell membrane proteins; red cell membrane stability and rigidity was normal on ektacytometry."
The negative result that defines this node: the membrane-skeleton mechanism of hereditary elliptocytosis was looked for in these patients and was not there.
PMID:27811305 SUPPORT Human Clinical
"Blood films revealed the presence of elliptocytes in the older brother."
The finding in an AMMECR1 point-mutation patient with COL4A5 intact, which is what ties it to this gene rather than to the wider deletion. Note it was present in one brother and not the other, which is where the variable expressivity of this feature shows.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

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Blood 1
Elliptocytosis HP:0004445 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elliptocytosis (HP:0004445). HP:0004445 is a phenotype from the Human Phenotype Ontology.
No frequency band; see the entry `notes`. Observed in the original AMME family (PMID:9598718), one of two point-mutation half-brothers (PMID:27811305), the X-linked elliptocytosis family where it was the presenting feature (PMID:28089922), the microdeletion pair (PMID:30737907) and the second missense case (PMID:42386221). The five-individual series explicitly describes the syndrome as occurring with *or without* elliptocytosis, so it is not obligate.
Show evidence (2 references)
PMID:28089922 SUPPORT Human Clinical
"In this study, we report a family with X-linked recessive syndrome caused by mutated AMMECR1 and characterized by elliptocytosis with or without anemia, midface hypoplasia, proportionate short stature and hearing loss."
The family in which elliptocytosis was the presenting feature, and the source for the "with or without anaemia" qualification.
PMID:29193635 REFUTE Human Clinical
"Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis."
Refutes elliptocytosis as an obligate feature. Recorded here rather than omitted because the disease name lists it, and a reader could otherwise take its absence as excluding the diagnosis.
Cardiovascular 1
Abnormal Heart Morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
No frequency band; see the entry `notes`. The source describes "cardiac and skeletal abnormalities" collectively across five individuals without specifying lesions, so the bound term is deliberately the general abnormal-heart-morphology term and nothing narrower is claimed.
Show evidence (1 reference)
PMID:29193635 SUPPORT Human Clinical
"They present with short stature, cardiac and skeletal abnormalities, and hearing loss."
The only source for cardiac involvement, and the reason the entry claims no specific cardiac lesion.
Ear 1
Sensorineural Hearing Impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407), qualified as course progressive; childhood onset. HP:0000407 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE Onset: CHILDHOOD
No frequency band; see the entry `notes`. Observed in the loss-of-function series (PMID:29193635), the microdeletion pair (PMID:30737907), the X-linked elliptocytosis family (PMID:28089922), the second missense case as partial hearing impairment (PMID:42386221), and in all three carrier females (PMID:35084080). The audiometric detail comes from the carrier report, so it describes carriers rather than affected males. The course is the clinically consequential part and it is not what a reader would assume from a congenital syndrome: the loss is postnatal in onset and progressive, so a normal audiogram in infancy does not exclude it. That is what makes repeated audiometry rather than a single screen the right diagnostic posture - see the Audiometry entry under `diagnosis`.
Show evidence (5 references)
PMID:30737907 SUPPORT Human Clinical
"In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small..."
Sensorineural hearing loss in two independent AMMECR1-deletion patients.
PMID:35084080 SUPPORT Human Clinical
"The audiograms showed mild to moderate SNHL with a variable pattern of the affected frequencies."
The audiometric characterisation, obtained in carrier females.
PMID:35084080 SUPPORT INDIRECT In Vitro
"Immunohistochemical analysis of fetal cochlea was performed confirming the expression of AMMECR1 in the human inner ear."
Places the gene product in the affected tissue. INDIRECT because expression in the cochlea does not by itself establish that its loss causes the hearing loss.
+ 2 more references
Genitourinary 2
Nephrocalcinosis HP:0000121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrocalcinosis (HP:0000121). HP:0000121 is a phenotype from the Human Phenotype Ontology.
No frequency band; see the entry `notes`. Observed in the point-mutation half-brothers, where it was the presenting problem (PMID:27811305), and in the second missense case (PMID:42386221). The first-report authors state the attribution cautiously, as AMMECR1 possibly playing a role, and that hedge is preserved here. How settled is this feature, given that it is in the disease name? Less than the name suggests, and the entry now says so with a `REFUTE` item rather than only in prose. The first-report authors wrote that the nephrocalcinosis "may be entirely incidental". Two things have changed since, and they cut in opposite directions. Against the caveat: their premise was that these findings were "unique to our study", and the 2026 second missense case reports nephrocalcinosis independently, so the finding is no longer unique. For the caveat: an independent recurrence in a second family is a much weaker claim than a mechanism, and none has been proposed. The honest position is that the association is now better supported than in 2016 and still not established, which is what the two evidence items below record. The same "may be entirely incidental" sentence also covers the submucous cleft palate and bifid uvula. It is quoted once, here, rather than repeated on the Cleft Palate phenotype - which carries a pointer to it in its own `notes:`.
Show evidence (4 references)
PMID:27811305 SUPPORT Human Clinical
"We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula."
Nephrocalcinosis as the presenting feature in the first AMMECR1 point-mutation family.
PMID:42386221 SUPPORT Human Clinical
"Here, we report a patient with a heterozygous de novo AMMECR1 missense variant, NM_015365.3:c.649G>A p.(Val217Met) presenting with clinical features consistent with MFHIEN, including midface hypoplasia, partial hearing impairment, nephrocalcinosis, and elliptocytosis identified on peripheral blood smear."
Independent recurrence of nephrocalcinosis with a second missense allele.
PMID:27811305 REFUTE Human Clinical
"Nephrocalcinosis, hypercalciuria, cataracts (in proband II(2)), submucous cleft palate and bifid uvula are unique to our study and may be entirely incidental; we do not have sufficient evidence in support of any causal relationship between AMMECR1 and these manifestations."
The first-report authors declining to attribute the nephrocalcinosis to AMMECR1 at all. It refutes the causal claim rather than the observation - the finding is real and repeatedly imaged in both half-brothers; what is contested is that AMMECR1 caused it. Recorded because nephrocalcinosis is in the disease name, so a reader would otherwise take the association as settled. Note the sentence's own premise ("unique to our study") is now superseded by the second missense case above.
+ 1 more reference
Hypercalciuria HP:0002150 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercalciuria (HP:0002150), qualified as temporality recurrent. HP:0002150 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
No frequency band; see the entry `notes`. Documented in one individual only - proband II(1) of PMID:27811305, where it was repeated and intermittent. It is not reported in his half brother II(2), who nonetheless had nephrocalcinosis from infancy, and their carrier mother was specifically tested and had no hypercalciuria. `temporality: RECURRENT` follows the source's word, "intermittent", rather than describing a sustained abnormality. The parenthesis in the "may be entirely incidental" sentence quoted on the Nephrocalcinosis phenotype attaches to the cataracts, not to the hypercalciuria - "cataracts (in proband II(2))" - so that sentence does not localise the hypercalciuria to either brother. The localisation here comes from the case narrative instead.
Sequelae: Nephrocalcinosis
Show evidence (2 references)
PMID:27811305 SUPPORT DIRECT Human Clinical
"He had repeatedly elevated urine calcium:creatinine ratios, but a persistently normal plasma calcium concentration."
The measurement, in proband II(1), and the normal plasma calcium that makes it a renal handling abnormality rather than a systemic one.
PMID:27811305 SUPPORT DIRECT Human Clinical
"He had persistent nephrocalcinosis with intermittent hypercalciuria."
The same proband at last review aged 11, with both findings persisting and the hypercalciuria described as intermittent.
Head and Neck 2
Midface Hypoplasia Midface retrusion HP:0011800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface hypoplasia, annotated with Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology.
No frequency band; see the entry `notes` for why. Observed in: the original AMME family (PMID:9598718), the first point-mutation half-brothers (PMID:27811305), the X-linked elliptocytosis family (PMID:28089922), the two array-CGH microdeletion patients (PMID:30737907) and the second missense case (PMID:42386221).
Show evidence (2 references)
PMID:27811305 SUPPORT Human Clinical
"Our study shows that a single missense mutation in AMMECR1 causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes, previously reported as part of a contiguous gene deletion syndrome."
Attributes midface hypoplasia to AMMECR1 specifically rather than to the contiguous deletion.
PMID:9598718 SUPPORT Human Clinical
"The two males presented with additional features including mental retardation, dysmorphic facies with marked midface hypoplasia, and elliptocytosis."
The original description, in the family that defined the phenotype.
Cleft Palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
No frequency band; see the entry `notes`. Observed in the point-mutation half-brothers as a submucous cleft with bifid uvula (PMID:27811305) and in one carrier female as a soft cleft palate (PMID:35084080). The bound term is the general cleft-palate term; `HP:0000176` for a submucous cleft would fit the first family but not the carrier, and the entry does not split a two-patient observation across two terms. The first-report authors' caveat that the submucous cleft palate and bifid uvula "may be entirely incidental" applies to this feature as well as to the nephrocalcinosis. It is quoted as a `REFUTE` item on the Nephrocalcinosis phenotype and is not repeated here; the carrier female's soft cleft palate, reported six years later in an unrelated family, is the independent observation that argues against reading it as coincidence.
Show evidence (2 references)
PMID:27811305 SUPPORT Human Clinical
"We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula."
The palatal finding in the first AMMECR1 point-mutation family.
PMID:35084080 SUPPORT Human Clinical
"All three women reported hearing loss and one was born with a soft cleft palate and hip dysplasia."
The same midline defect in a carrier female.
Limbs 1
Congenital Hip Dysplasia Congenital hip dislocation HP:0001374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital hip dysplasia, annotated with Congenital hip dislocation (HP:0001374). HP:0001374 is a phenotype from the Human Phenotype Ontology.
No frequency band; see the entry `notes`. The carrier report names hip dysplasia in one of three women and states that it had been reported before in male AMMECR1 point-mutation carriers. The bound HP term is `Congenital hip dislocation`, which is HPO's label for this concept; `preferred_term` keeps the clinical wording used in the source.
Show evidence (1 reference)
PMID:35084080 SUPPORT Human Clinical
"Previously, mutations in the AMMECR1 gene have been described in six males with developmental delay, sensorineural hearing loss (SNHL) and/or congenital abnormalities, including fetal nuchal edema, fetal pericardial effusion, talipes, congenital hip dysplasia, elliptocytosis and cleft palate."
Places hip dysplasia among the previously reported male findings, and incidentally lists the fetal findings - nuchal edema, pericardial effusion, talipes - that are part of the wider spectrum but are not separately curated here.
Musculoskeletal 1
Infantile Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile hypotonia, annotated with Hypotonia (HP:0001252), qualified as neonatal onset. HP:0001252 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
No frequency band; see the entry `notes`. Present in proband II(1) of PMID:27811305 and explicitly absent in his half-brother II(2), who met his motor milestones - one of the clearest instances of variable expressivity in this disease, in two boys carrying the same allele. The first-report authors also suggest part of it may be secondary to the joint hypermobility that persisted through childhood, which is a caveat rather than an alternative explanation and is not curated as a separate mechanism. Bound to `HP:0001252` (Hypotonia) with the infantile qualifier carried by `preferred_term` and the `onset` descriptor, rather than to `HP:0008947`. That term was suggested in review as "the infantile form", but its canonical HPO label is `Floppy infant` - a specific severe neonatal presentation - and the source describes hypotonia with poor feeding that later improved, which is not the same claim. Binding the parent term and qualifying it keeps the entry from asserting more than the case narrative does.
Show evidence (2 references)
PMID:27811305 SUPPORT DIRECT Human Clinical
"Shortly after birth, proband II(1) was noted to have hypotonia and poor feeding."
The onset observation, attributed to the older half-brother.
PMID:27811305 SUPPORT DIRECT Human Clinical
"Proband II(1) had significant infantile hypotonia1 and delay in gross motor skills in addition."
The authors' own summary of the finding in the discussion. The stray "1" is a reference marker in the source text and is retained so the quote matches the cache exactly.
Nervous System 1
Developmental Delay and Intellectual Disability Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
No frequency band; see the entry `notes`. Observed in the original AMME family (PMID:9598718), the point-mutation half-brothers as speech and language delay (PMID:27811305) and the microdeletion pair as mild intellectual disability or neurodevelopmental delay (PMID:30737907). The bound term is the developmental-delay term rather than the intellectual-disability term because several reports describe delay in young children rather than an established cognitive outcome.
Show evidence (2 references)
PMID:30737907 SUPPORT Human Clinical
"In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small..."
Records both the delay and its mildness in two independent deletion patients.
PMID:27811305 SUPPORT Human Clinical
"We conclude that AMMECR1 is a critical gene in the pathogenesis of AMME, causing midface hypoplasia and elliptocytosis and contributing to early speech and language delay, infantile hypotonia and hearing loss, and may play a role in dysmorphism, nephrocalcinosis and submucous cleft palate."
The authors' graded attribution across features - "causing" for two, "contributing to" for three, "may play a role" for three more - which is the source of the hedging used throughout this entry.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
No frequency band; see the entry `notes`. Observed in the five-individual loss-of-function series (PMID:29193635), the microdeletion pair (PMID:30737907) and the X-linked elliptocytosis family, where it is specified as proportionate (PMID:28089922).
Show evidence (1 reference)
PMID:29193635 SUPPORT Human Clinical
"They present with short stature, cardiac and skeletal abnormalities, and hearing loss."
The core phenotype of the largest reported series.
🧬

Genetic Associations

1
AMMECR1
Gene: AMMECR1 hgnc:467 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is AMMECR1 (hgnc:467). hgnc:467 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:10049589 SUPPORT Other
"Exon 2 of AMMECR1 encodes a domain consisting of six amino acids identically conserved throughout the course of evolution and whose function is as yet unknown."
The deep conservation that made the gene a plausible candidate, together with the statement that its function was unknown - which has not since been resolved.
PMID:30737907 SUPPORT Human Clinical
"In these cases, AMMECR1 gene appears to be responsible for most of the clinical features of the AMME syndrome except for Alport syndrome."
The gene-disease assignment stated exactly: AMMECR1 carries the AMME phenotype minus its renal component.
PMID:42386221 SUPPORT Human Clinical
"Additional cases and functional studies are needed to clarify genotype-phenotype correlations and underlying disease mechanisms."
The current state of the gene-disease relationship in its authors' words, and the reason this entry asserts no correlation between allele type and phenotype.
💊

Medical Actions

3
Hearing aid usage
Platform: Device
Amplification for the sensorineural hearing loss. In the first point-mutation family the older half-brother had bilateral mixed hearing loss requiring hearing aids, and the authors attribute part of his subsequent speech and language improvement to the correction of his hearing and palate together. This is phenotype-directed and not disease-modifying, which is the only kind of treatment this entity has: nothing is known about what AMMECR1 does, so there is no mechanism to aim at. Because the loss is progressive rather than static, the clinical decision is not a one-off fitting but repeat audiometry with amplification adjusted as thresholds move - see the Audiometry entry under `diagnosis`.
Target Phenotypes: Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27811305 SUPPORT DIRECT Human Clinical
"He had bilateral mixed hearing loss requiring hearing aids"
The intervention as reported in proband II(1).
PMID:27811305 SUPPORT INDIRECT Human Clinical
"Both abnormalities were corrected (with hearing aids and cleft palate repair), which may explain the improvement in speech and language development."
The outcome the authors attribute to amplification and palate repair together. INDIRECT because it is an uncontrolled single-family observation and the source hedges it - "may explain" - and because the two interventions are not separable in it.
Cleft palate repair
Action: cleft palate repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cleft palate repair, annotated with Palatorrhaphy (NCIT:C168380). NCIT:C168380 is a clinical intervention from the NCI Thesaurus. Ontology label: Palatorrhaphy NCIT:C168380
Platform: Surgery
Surgical closure of the submucous cleft palate and bifid uvula. Both point-mutation half-brothers had the palatal defect and the older one underwent surgical correction; his feeding and gross motor development improved afterwards, and the authors name the repair as one of two corrections that may account for his speech and language gains.
Target Phenotypes: Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27811305 SUPPORT DIRECT Human Clinical
"He had surgical correction for a submucous cleft palate and bifid uvula."
The procedure as reported in proband II(1).
PMID:27811305 SUPPORT INDIRECT Human Clinical
"He was discharged from physiotherapy, occupational therapy and speech and language therapy before his second birthday, having made improvements in his gross motor development and feeding following cleft palate repair."
The reported outcome. INDIRECT: an uncontrolled observation in one child, with the developmental improvement temporally associated with the repair rather than shown to follow from it.
Pavlik harness for congenital hip dysplasia
Platform: Device
Abduction bracing for the congenital hip dysplasia, applied in proband II(2). Curated because hip dysplasia is one of this entry's phenotypes and this is the only management of it any source reports; no outcome is given.
Target Phenotypes: Congenital hip dysplasia HP:0001374 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congenital hip dysplasia, annotated with Congenital hip dislocation (HP:0001374). HP:0001374 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27811305 SUPPORT DIRECT Human Clinical
"He had congenital dysplasia of the hips treated with a Pavlik harness."
The intervention as reported in proband II(2).
🔬

Diagnosis

3
Peripheral blood smear for elliptocytes
Examination of the blood film is the step most likely to be skipped, and it is the one that turns a nonspecific dysmorphic-and-delayed presentation into a recognisable syndrome. The most recent case report makes exactly this point: the elliptocytosis was found on smear and the authors argue for pairing detailed phenotyping, haematology included, with the genomic data. Note the smear can be normal - one of the two point-mutation half-brothers had elliptocytes and the other did not.
peripheral blood smear examination NCIT:C124351 NCI Thesaurus (NCIT)
Results: Elliptocytes on the peripheral film, with or without anaemia; a normal smear does not exclude the diagnosis.
The bound NCIT term is the general Clinical Evaluation term. NCIT's `Blood Smear` term (NCIT:C79903) names the specimen rather than a clinical action and is not reachable from NCIT:C25218, so it cannot sit in this slot; `preferred_term` carries the specificity instead.
Show evidence (1 reference)
PMID:42386221 SUPPORT Human Clinical
"emphasize the importance of integrating detailed phenotyping, including hematologic evaluation, with genomic data in the diagnosis of rare multisystem disorders"
The authors' explicit diagnostic recommendation, naming haematology.
Audiometry
Hearing loss is sensorineural, mild to moderate where audiograms are reported, and the affected frequencies vary between individuals - so a normal impression on casual testing is not sufficient, and carriers should be tested too rather than asked.
audiometric assessment NCIT:C124351 NCI Thesaurus (NCIT)
Results: Mild to moderate sensorineural hearing loss with a variable pattern of affected frequencies. A normal audiogram does not exclude the diagnosis and should be repeated.
Longitudinal audiometry, not a single screen. The hearing loss is postnatal in onset and progressive - one proband had a normal audiogram at 2 and detectable sensorineural loss at 3, and his half-brother's audiogram at 4 had deteriorated from a previous one while still reading within the normal range on air conduction. So a normal or borderline result in an infant or toddler carries almost no information, and the practical recommendation is repeat testing through childhood. Carriers should be tested rather than asked: all three carrier females in PMID:35084080 reported hearing loss and had it confirmed audiometrically.
Show evidence (2 references)
PMID:35084080 SUPPORT Human Clinical
"The audiograms showed mild to moderate SNHL with a variable pattern of the affected frequencies."
The audiometric findings, and the basis for the variability caveat.
PMID:27811305 SUPPORT DIRECT Human Clinical
"sensorineural hearing loss was first detected at age 3, despite a normal audiogram 1 year previously"
The observation that makes this a surveillance test rather than a one-off one: a normal audiogram at age 2 did not exclude the diagnosis in the same child a year later.
Molecular testing for AMMECR1 variants and Xq22.3 copy number
Two testing modalities are needed rather than one, because the reported lesions split between sequence variants and copy number. Exome sequencing found the point mutations; array-CGH found the microdeletions, including small ones covering only TMEM164, AMMECR1 and SNORD96B. A sequencing-only workup would miss the deletion patients, and a copy-number-only workup would miss the missense ones. Where a deletion is found, its extent relative to COL4A5 is what decides whether the patient also has Alport syndrome.
molecular analysis NCIT:C19770 NCI Thesaurus (NCIT)
Results: A hemizygous AMMECR1 sequence variant, or a deletion involving AMMECR1, with maternal carrier testing where informative.
Show evidence (2 references)
PMID:27811305 SUPPORT Human Clinical
"Whole exome sequencing was undertaken on maternal half-siblings."
The sequencing route, in the family where the first point mutation was found.
PMID:30737907 SUPPORT Human Clinical
"In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small..."
The copy-number route, and the source for the claim that the deletions can be small enough to escape a sequencing-only workup.
📊

Prevalence

1
Cases reported in the literature worldwide
Cases In Literature Unknown
Roughly a dozen affected males across six reports as of 2026, plus three carrier females. The carrier report counts six males with point mutations described previously and ten with a deletion including AMMECR1. No population prevalence has been published and none is estimated here.
Show evidence (2 references)
PMID:35084080 SUPPORT Human Clinical
"Previously, mutations in the AMMECR1 gene have been described in six males with developmental delay, sensorineural hearing loss (SNHL) and/or congenital abnormalities, including fetal nuchal edema, fetal pericardial effusion, talipes, congenital hip dysplasia, elliptocytosis and cleft palate."
The published count of point-mutation males as of that report.
PMID:35084080 SUPPORT Human Clinical
"Until now, 10 male patients with a deletion including AMMECR1 have been described"
The published count of deletion males as of that report.
🐁

Animal Models

1
Zebrafish ammecr1 morphant
The only animal work on this gene in the sources read here. Knocking down the zebrafish orthologue produced phenotypes the authors describe as reminiscent of the patients' features - which is a similarity claim, not a phenotype-by-phenotype recapitulation, and is treated as such below.
Species
Zebrafish
Genotype
knockdown of the zebrafish AMMECR1 orthologue
Publication
PMID:29193635
Pathograph links
Disturbed Cell-Cycle-Associated Program in Developing Tissues partially recapitulates fidelity: low Establishes that the gene is required for normal development in a vertebrate, which is the main thing this node needs and nearly the only thing the model supplies.
Limitations: The phenotypes are characterised only as "reminiscent" of the human features, with no individual correspondence reported; knockdown is not the same lesion as the human microdeletions and point mutations; and no cell-cycle measurement was made in the fish, so the model does not test the mechanism this node proposes. Zebrafish also have no midface in the sense the human phenotype uses, so the syndrome's defining feature cannot be assessed in it at all.
Show evidence (1 reference)
PMID:29193635 SUPPORT Model Organism
"Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features."
The whole of the reported animal result, quoted at the strength it is stated.
{ }

Source YAML

click to show 
name: Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis
category: Mendelian
creation_date: "2026-09-04T00:00:00Z"
synonyms:
- MFHIEN
- MHEN
- AMMECR1-related syndrome
- AMMECR1 nuclear protein 1-related X-linked syndrome
description: >-
  This is the disease that was left over when a contiguous-gene deletion syndrome was taken
  apart. AMME - Alport syndrome, intellectual disability, midface hypoplasia and elliptocytosis -
  was described in 1998 as an Xq22.3 microdeletion spanning COL4A5 and its neighbours. COL4A5
  explained the Alport syndrome and nothing else, so the remaining features had to belong to a
  neighbouring gene. AMMECR1 was cloned out of the deleted interval the following year and named
  for the syndrome, with no known function.

  Two decades later the assignment was confirmed from the other direction: point mutations and
  microdeletions that hit AMMECR1 but spare COL4A5 reproduce the non-renal AMME features and not
  Alport syndrome. What is left is this entity - midface hypoplasia, sensorineural hearing loss,
  elliptocytosis and nephrocalcinosis, usually with short stature and developmental delay, and in
  the larger series with cardiac and skeletal abnormalities as well.

  The mechanism is genuinely open, and the entry says so rather than dressing it up. AMMECR1 is a
  nuclear protein with a nucleic-acid-binding RAGNYA fold that dimerizes with its paralog
  AMMECR1L; it is coexpressed with cell-cycle genes, several of which have their own growth and
  bone phenotypes, and its authors put this no more strongly than "potentially involved in cell
  cycle control". The one functional handle on a patient allele is localisation: the p.G177D
  missense protein distributes abnormally within the nucleus. How any of that produces midface
  hypoplasia or renal calcification is not known.

  One negative result deserves to survive from the original 1998 report, because it rules out the
  obvious explanation for the blood finding. The elliptocytosis here is not hereditary
  elliptocytosis: red cell membrane proteins were normal, and membrane stability and rigidity
  were normal on ektacytometry. Whatever deforms the red cells, it is not the spectrin-actin
  membrane skeleton defect that carries that name in haematology.
disease_term:
  preferred_term: midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis
  term:
    id: MONDO:0010516
    label: midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis
parents:
- X-linked Mendelian disease
notes: >-
  Identifiers. OMIM #300990 (MFHIEN) and OMIM 300195 (AMMECR1); the parent contiguous-gene
  syndrome AMME is OMIM 300194. Recorded in prose because the schema's `mappings` block carries
  `mondo_mappings` only and has no OMIM slot.

  Relationship to AMME and to Alport syndrome. This entry is the AMMECR1-attributable part of the
  AMME phenotype, and deliberately not AMME itself. AMME is a contiguous-gene deletion syndrome
  whose renal component comes from COL4A5; a patient whose deletion removes both genes has
  Alport syndrome as well, and that belongs to the Alport entries in this KB rather than here.
  The nephrocalcinosis curated below is a separate finding from Alport nephropathy and is
  reported in patients whose COL4A5 is intact.

  Why no phenotype carries a frequency band. The published experience is roughly a dozen affected
  males spread across six reports, and no two reports ascertain the same way: one is a
  nephrocalcinosis-led pair of half-brothers, one a growth-and-bone series, one a pair of
  array-CGH microdeletions, one a family reported for elliptocytosis, one a single missense case.
  There is no cohort and therefore no denominator, so every phenotype below records which reports
  observed it in `notes` instead of carrying a manufactured band. Assigning bands across
  incommensurable case reports would produce numbers that look like frequencies and are not.

  Evidence base. Six PMIDs: the founding contiguous-gene description (PMID:9598718), the cloning
  of AMMECR1 out of the deleted interval (PMID:10049589), the first point mutation with
  functional work (PMID:27811305), a second family reported as X-linked elliptocytosis with
  impaired growth (PMID:28089922), the five-individual loss-of-function series with the zebrafish
  knockdown (PMID:29193635), two AMMECR1-only microdeletions (PMID:30737907), the female-carrier
  report with fetal cochlear immunohistochemistry (PMID:35084080), and the second missense case
  (PMID:42386221).

  A corrigendum to PMID:28089922 was published as PMID:29174631. It has no fetchable abstract, so
  nothing is cited from it and no claim here rests on it; it is named so a reader checking that
  paper knows the correction exists.

  What is not asserted. No mechanism is claimed between AMMECR1 loss and any individual
  phenotype: the causal edges below are typed as having unknown intermediates and say so in their
  descriptions. No genotype-phenotype correlation is asserted - the most recent report states
  that additional cases and functional studies are needed to establish one.

  Treatments. An earlier draft of this entry carried no `treatments:` block and said no source
  described an intervention. That was wrong and is corrected here: the first point-mutation
  report describes hearing aids and submucous cleft palate repair in proband II(1), with a
  reported outcome, and those are now curated. What remains true is the reason the block looked
  unnecessary - there is no disease-modifying treatment and there cannot yet be one, because the
  gene's function is unknown. Both entries are phenotype-directed, both join the pathograph
  through `target_phenotypes` rather than `target_mechanisms`, and none should be read as acting
  on a mechanism. One intervention in the source is deliberately not curated: the bilateral
  percutaneous achilles tenotomies proband II(1) had at two months, because the talipes they
  treated is not curated as a phenotype in this entry - it appears only inside a quoted list of
  previously reported findings.

  Deep research. A Falcon deep-research report is committed alongside this entry. It passed
  `just preflight-dr` against MONDO:0010516 with AMMECR1 mentioned 41 times, the correct OMIM
  number recovered independently, and COL4A5 a distant second at 9 - which for this disease is
  the right shape, since COL4A5 is the neighbouring gene the entity had to be separated from.
  Reference validation resolved 4 of 4 citations with a confabulation rate of 0, and term
  validation resolved 29 of 30 with none unresolved. The report was used as a lead source only -
  every snippet below is anchored to a PMID fetched into `references_cache/` and read directly.
inheritance:
- name: X-linked recessive
  description: >-
    Affected individuals are males hemizygous for an AMMECR1 point mutation or microdeletion,
    typically inherited from an unaffected or mildly affected mother; de novo variants are also
    reported.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:28089922
    reference_title: X-linked elliptocytosis with impaired growth is related to mutated AMMECR1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we report a family with X-linked recessive syndrome caused by mutated AMMECR1 and characterized by elliptocytosis with or without anemia, midface hypoplasia, proportionate short stature and hearing loss."
    explanation: States the inheritance pattern and the core phenotype in one sentence.
  - reference: PMID:29193635
    reference_title: Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants."
    explanation: >-
      The allelic and inheritance spectrum across five individuals, including maternal
      transmission, a de novo variant, and the X-autosome translocation case.
- name: X-linked, with a partial phenotype in female carriers
  description: >-
    Carrier females are not uniformly unaffected. Three female relatives of a male fetus carrying
    an intragenic AMMECR1 deletion all reported hearing loss, with mild to moderate sensorineural
    loss on audiometry, and one had a soft cleft palate and hip dysplasia. This is recorded as a
    separate inheritance entry rather than folded into the recessive one, because it changes what
    a carrier should be told.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  evidence:
  - reference: PMID:35084080
    reference_title: Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three women reported hearing loss and one was born with a soft cleft palate and hip dysplasia."
    explanation: The carrier findings themselves.
  - reference: PMID:35084080
    reference_title: Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we suggest that female carriers may display a partial phenotype in this X-linked condition"
    explanation: >-
      The authors' own conclusion, stated as a suggestion rather than an established rule, which
      is how it is recorded here.
pathophysiology:
- name: AMMECR1 Loss of Function
  description: >-
    The initiating lesion. Reported alleles span the range: microdeletions removing AMMECR1 alone
    or with its immediate neighbours TMEM164 and SNORD96B, nonsense variants, an X-autosome
    translocation with skewed inactivation of the normal X, and missense changes. AMMECR1 sits in
    the Xq22.3 interval deleted in AMME, and the disease-defining observation is that variants
    hitting AMMECR1 while sparing COL4A5 reproduce the non-renal AMME features without Alport
    syndrome.

    The gene encodes a 35.5 kDa protein from six exons with a ubiquitous transcript, conserved
    from yeast and nematode upward. When it was cloned, its function was unknown; a conserved
    six-amino-acid domain in exon 2 was noted with function unknown then, and it remains
    substantially unknown now.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: AMMECR1
    term:
      id: hgnc:467
      label: AMMECR1
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    description: >-
      Hemizygous in affected males - microdeletion, nonsense or missense. The functional impact
      is recorded as loss of function because the microdeletion and nonsense alleles are
      unambiguous and produce the same phenotype as the missense ones; whether every missense
      allele acts by simple loss of function is not established.
  downstream:
  - target: Loss of Nuclear AMMECR1 Function
    description: >-
      Deleting the gene removes the protein outright; the studied missense allele leaves the
      protein present but abnormally distributed within the nucleus. Both routes converge on the
      absence of normal nuclear AMMECR1 activity.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the affected half-brothers, we identified a hemizygous novel non-synonymous variant of unknown significance in AMMECR1 (c.G530A; p.G177D), a gene residing in the AMME disease locus."
    explanation: >-
      The first point mutation in the gene, in the family that separated AMMECR1's contribution
      from the rest of the AMME deletion.
  - reference: PMID:30737907
    reference_title: "Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These original cases further confirm that most specific AMME features are ascribed to AMMECR1 haploinsufficiency."
    explanation: >-
      Independent confirmation from the deletion side that this gene, not its neighbours, carries
      the non-renal phenotype.
  - reference: PMID:10049589
    reference_title: "Identification and characterization of a highly conserved protein absent in the Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E) contiguous gene deletion syndrome (AMME)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AMMECR1 is composed of six exons, shows a ubiquitous 6.5-kb transcript, and codes for a protein with a molecular mass of 35.5 kDa."
    explanation: >-
      The gene's basic architecture, from the report that cloned it out of the AMME deletion
      interval. Graded OTHER because this is molecular cloning and sequence analysis rather than
      any of the study types the other values name.
- name: Loss of Nuclear AMMECR1 Function
  description: >-
    AMMECR1 and its paralog AMMECR1L dimerize and localize to the nucleus, which their
    nucleic-acid-binding RAGNYA folds would predict. The one patient allele examined functionally,
    p.G177D, is not absent from the nucleus but distributed abnormally within it - and the second
    reported missense allele is described the same way, as altered intranuclear distribution with
    reduced expression.

    What the protein does there is unresolved. The strongest statement its investigators make is
    that it is potentially involved in cell cycle control, inferred from coexpression rather than
    from an assay of AMMECR1 itself. This node therefore records a demonstrated molecular
    abnormality with an undetermined downstream function, which is the honest shape of the
    evidence.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: nucleus
    term:
      id: GO:0005634
      label: nucleus
  molecular_functions:
  - preferred_term: nucleic acid binding, predicted from the RAGNYA fold
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0003676
      label: nucleic acid binding
  downstream:
  - target: Disturbed Cell-Cycle-Associated Program in Developing Tissues
    description: >-
      The proposed consequence, and the weakest link in this chain. It rests on AMMECR1's
      coexpression with cell-cycle genes and on the zebrafish knockdown phenotype, not on any
      measurement of cell-cycle progression in patient cells.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Elliptocytosis Without a Membrane Skeleton Defect
    description: >-
      Drawn separately from the developmental branch because the original family's red cells were
      shown *not* to have the membrane defect that ordinarily causes elliptocytosis, so this is
      not a downstream consequence of any established mechanism. The edge records that the blood
      phenotype tracks AMMECR1 loss; its intermediates are unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:29193635
    reference_title: Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    snippet: "AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds."
    explanation: >-
      The structural and localisation account of the normal protein. Graded COMPUTATIONAL because
      the nucleic-acid-binding function is a fold-based prediction, and INDIRECT because it
      describes the wild-type protein rather than a patient allele.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Transfected cell lines with the p.G177D mutation showed aberrant nuclear localisation patterns when compared with the wild type."
    explanation: >-
      The only direct functional demonstration for a patient allele: the mutant protein
      mislocalises within the nucleus in transfected cells.
  - reference: PMID:42386221
    reference_title: "A Second Report of a Missense Variant in AMMECR1 Causing Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis: Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Comparative review of the literature highlights that while previously reported missense variants in AMMECR1 demonstrated altered intranuclear protein distribution and reduced expression in functional assays, clinical evidence supporting pathogenicity of non-truncating variants remains limited."
    explanation: >-
      Confirms the intranuclear-distribution finding generalises across the reported missense
      alleles, and carries the authors' caveat about how thin the clinical evidence for
      non-truncating variants still is.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "The expression pattern of mutated AMMECR1 we observed within the nucleus is consistent with the altered protein being targeted for degradation by this system."
    explanation: >-
      The authors' proposed route from the missense allele to loss of nuclear function -
      proteasomal degradation of the mal-folded protein, inferred from the mutant's resemblance
      to nuclear 20S proteasome staining and from reduced GFP expression. INDIRECT because it is
      an interpretation of a localisation pattern, and the source hedges it throughout
      ("consistent with", "may therefore be"); no degradation assay was performed. It is recorded
      on this node rather than as a node of its own, because a separate proteasomal node would
      give a speculative step the same graph weight as the measured mislocalisation.
- name: Disturbed Cell-Cycle-Associated Program in Developing Tissues
  description: >-
    The proposed bridge between a nuclear protein of unknown function and a multisystem
    developmental phenotype. AMMECR1 is coexpressed with genes implicated in cell cycle
    regulation, five of which already have growth and bone phenotypes of their own, and knocking
    down the zebrafish orthologue produces features reminiscent of the patients'. That is the
    entire basis; no cell-cycle measurement has been made in patient material, and the proposal
    is stated by its authors as a possibility.

    Recorded as a node anyway, because the alternative is a graph in which a gene deletion
    connects directly to seven unrelated clinical findings with nothing in between, which would
    misrepresent the literature in the opposite direction.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: cell cycle control, proposed rather than demonstrated
    modifier: DYSREGULATED
    term:
      id: GO:0007049
      label: cell cycle
  mechanism_confidence: HYPOTHETICAL
  downstream:
  - target: Midface Hypoplasia
    description: >-
      The facial phenotype that named the syndrome. No mechanism connecting AMMECR1 to midfacial
      growth has been proposed in any source read here.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural Hearing Impairment
    description: >-
      The one phenotype with a tissue-level foothold: AMMECR1 protein is expressed in the human
      fetal cochlea, so the gene is present where the deficit appears. Expression is not
      mechanism, and nothing further is claimed.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Short Stature
    description: >-
      Proportionate short stature is one of the most consistent features across reports, and the
      growth phenotype is what led to the cell-cycle coexpression hypothesis in the first place.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Developmental Delay and Intellectual Disability
    description: >-
      The "mental retardation" of the original AMME acronym, now attributed to AMMECR1 rather
      than to COL4A5 or the wider deletion.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Heart Morphology
    description: >-
      Cardiac abnormalities appear in the five-individual loss-of-function series and are not
      reported in the earlier families, which is why they are curated as part of the spectrum
      rather than as a core feature.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cleft Palate
    description: >-
      Midline palatal defects - a submucous cleft with bifid uvula in the first point-mutation
      family, a soft cleft palate in a female carrier - alongside the midface hypoplasia, which is
      what makes the facial phenotype a midline developmental one rather than isolated retrusion.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Congenital Hip Dysplasia
    description: >-
      Part of the skeletal component, reported both in affected males and in a carrier female.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nephrocalcinosis
    description: >-
      The renal finding that is *not* Alport syndrome. It was the presenting problem in the first
      point-mutation family and recurs in the most recent missense case, but its investigators put
      the attribution no more strongly than that AMMECR1 may play a role in it.

      This edge is kept alongside the hypercalciuria route below rather than replaced by it,
      because the second half-brother's nephrocalcinosis has no reported hypercalciuria at all.
      Whatever the calcium-handling route explains, it does not explain every reported case.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypercalciuria
    description: >-
      Excessive urinary calcium excretion with a normal plasma calcium - so a renal tubular
      handling problem rather than a systemic hypercalcaemia. It is the only candidate
      intermediate any source offers for the renal phenotype, and it is why the first-report
      authors screened a panel of idiopathic-hypercalciuria genes before settling on AMMECR1.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Infantile Hypotonia
    description: >-
      Hypotonia from shortly after birth in one of the two point-mutation half-brothers, listed
      by the first-report authors among the features AMMECR1 loss contributes to. Explicitly
      absent in his half-brother, who met his motor milestones - so this edge describes a
      variably expressed consequence, not a constant one.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:29193635
    reference_title: Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    snippet: "AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations."
    explanation: >-
      The coexpression analysis that generated the hypothesis. COMPUTATIONAL and INDIRECT: it is
      a transcriptomic association, and the inference to cell-cycle involvement is one step
      beyond what it measures.
  - reference: PMID:29193635
    reference_title: Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features."
    explanation: >-
      The animal evidence that the gene is required for normal development. "Reminiscent" is the
      authors' word and is not upgraded here.
  - reference: PMID:29193635
    reference_title: Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis."
    explanation: >-
      The authors' summary claim, at the strength they state it - "potentially involved" - which
      is why this node's `mechanism_confidence` is HYPOTHETICAL.
- name: Elliptocytosis Without a Membrane Skeleton Defect
  description: >-
    Elliptical red cells on the blood film, sometimes with anaemia. The important thing about this
    finding is what it is not: in the original AMME family the elliptocytosis was not accompanied
    by any detectable abnormality of red cell membrane proteins, and membrane stability and
    rigidity were normal on ektacytometry - the assay that is abnormal in hereditary
    elliptocytosis. So the shared name with hereditary elliptocytosis is a morphological
    coincidence, not a shared mechanism, and no mechanism has since been proposed.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  mechanism_confidence: HYPOTHETICAL
  downstream:
  - target: Elliptocytosis
    description: The morphological finding itself, as seen on the peripheral blood smear.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:9598718
    reference_title: "Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis: a new X linked contiguous gene deletion syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The elliptocytosis was not associated with any detectable abnormalities in red cell membrane proteins; red cell membrane stability and rigidity was normal on ektacytometry."
    explanation: >-
      The negative result that defines this node: the membrane-skeleton mechanism of hereditary
      elliptocytosis was looked for in these patients and was not there.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood films revealed the presence of elliptocytes in the older brother."
    explanation: >-
      The finding in an AMMECR1 point-mutation patient with COL4A5 intact, which is what ties it
      to this gene rather than to the wider deletion. Note it was present in one brother and not
      the other, which is where the variable expressivity of this feature shows.
phenotypes:
- name: Midface Hypoplasia
  category: Craniofacial
  description: >-
    Underdevelopment of the midface, the feature that supplies the first M of AMME and the first
    words of this entity's name.
  phenotype_term:
    preferred_term: Midface hypoplasia
    term:
      id: HP:0011800
      label: Midface retrusion
  notes: >-
    No frequency band; see the entry `notes` for why. Observed in: the original AMME family
    (PMID:9598718), the first point-mutation half-brothers (PMID:27811305), the X-linked
    elliptocytosis family (PMID:28089922), the two array-CGH microdeletion patients
    (PMID:30737907) and the second missense case (PMID:42386221).
  evidence:
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study shows that a single missense mutation in AMMECR1 causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes, previously reported as part of a contiguous gene deletion syndrome."
    explanation: >-
      Attributes midface hypoplasia to AMMECR1 specifically rather than to the contiguous
      deletion.
  - reference: PMID:9598718
    reference_title: "Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis: a new X linked contiguous gene deletion syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two males presented with additional features including mental retardation, dysmorphic facies with marked midface hypoplasia, and elliptocytosis."
    explanation: The original description, in the family that defined the phenotype.
- name: Sensorineural Hearing Impairment
  category: Auditory
  description: >-
    Sensorineural hearing loss, mild to moderate where audiograms are reported, with a variable
    pattern of affected frequencies. It is one of the few features with any tissue-level support:
    AMMECR1 is expressed in the human fetal inner ear.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
    clinical_course: PROGRESSIVE
    onset:
      onset_category: CHILDHOOD
      notes: >-
        Both onset qualifiers come from the two point-mutation half-brothers of PMID:27811305 and
        from nowhere else. In the older proband sensorineural loss was first detected at age 3
        with a normal audiogram a year earlier; in the younger, an audiogram at 4 showed
        deterioration from a previous one. The authors read that pair of observations as
        progressive hearing loss without congenital onset. Age of detection is not the same as
        age of onset, and no other report gives an age at all, so `CHILDHOOD` records where the
        only dated observations fall rather than a spectrum-wide onset claim.
  notes: >-
    No frequency band; see the entry `notes`. Observed in the loss-of-function series
    (PMID:29193635), the microdeletion pair (PMID:30737907), the X-linked elliptocytosis family
    (PMID:28089922), the second missense case as partial hearing impairment (PMID:42386221), and
    in all three carrier females (PMID:35084080). The audiometric detail comes from the carrier
    report, so it describes carriers rather than affected males.

    The course is the clinically consequential part and it is not what a reader would assume from
    a congenital syndrome: the loss is postnatal in onset and progressive, so a normal audiogram
    in infancy does not exclude it. That is what makes repeated audiometry rather than a single
    screen the right diagnostic posture - see the Audiometry entry under `diagnosis`.
  evidence:
  - reference: PMID:30737907
    reference_title: "Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers."
    explanation: Sensorineural hearing loss in two independent AMMECR1-deletion patients.
  - reference: PMID:35084080
    reference_title: Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The audiograms showed mild to moderate SNHL with a variable pattern of the affected frequencies."
    explanation: The audiometric characterisation, obtained in carrier females.
  - reference: PMID:35084080
    reference_title: Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Immunohistochemical analysis of fetal cochlea was performed confirming the expression of AMMECR1 in the human inner ear."
    explanation: >-
      Places the gene product in the affected tissue. INDIRECT because expression in the cochlea
      does not by itself establish that its loss causes the hearing loss.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "His audiogram shows deterioration from one previously, suggesting a progressive pattern of hearing loss without congenital onset."
    explanation: >-
      The source for `clinical_course: PROGRESSIVE` and for the postnatal onset, stated by the
      authors about the younger half-brother.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "sensorineural hearing loss was first detected at age 3, despite a normal audiogram 1 year previously"
    explanation: >-
      The older half-brother's course, and the observation that makes a single normal audiogram
      insufficient to exclude the diagnosis.
- name: Elliptocytosis
  category: Hematologic
  description: >-
    Elliptical red cells on the peripheral smear, with or without anaemia, and without the
    membrane-protein defect of hereditary elliptocytosis. Expressivity is variable even within a
    sibship - it was present in one of the two point-mutation half-brothers.
  phenotype_term:
    preferred_term: Elliptocytosis
    term:
      id: HP:0004445
      label: Elliptocytosis
  notes: >-
    No frequency band; see the entry `notes`. Observed in the original AMME family
    (PMID:9598718), one of two point-mutation half-brothers (PMID:27811305), the X-linked
    elliptocytosis family where it was the presenting feature (PMID:28089922), the microdeletion
    pair (PMID:30737907) and the second missense case (PMID:42386221). The five-individual series
    explicitly describes the syndrome as occurring with *or without* elliptocytosis, so it is not
    obligate.
  evidence:
  - reference: PMID:28089922
    reference_title: X-linked elliptocytosis with impaired growth is related to mutated AMMECR1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we report a family with X-linked recessive syndrome caused by mutated AMMECR1 and characterized by elliptocytosis with or without anemia, midface hypoplasia, proportionate short stature and hearing loss."
    explanation: >-
      The family in which elliptocytosis was the presenting feature, and the source for the
      "with or without anaemia" qualification.
  - reference: PMID:29193635
    reference_title: Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis."
    explanation: >-
      Refutes elliptocytosis as an obligate feature. Recorded here rather than omitted because
      the disease name lists it, and a reader could otherwise take its absence as excluding the
      diagnosis.
- name: Nephrocalcinosis
  category: Renal
  description: >-
    Calcium deposition in the renal parenchyma. This is the renal finding that belongs to
    AMMECR1; it is distinct from the Alport nephropathy of the contiguous-gene AMME deletion,
    which comes from COL4A5 and is not part of this entity.
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  notes: >-
    No frequency band; see the entry `notes`. Observed in the point-mutation half-brothers, where
    it was the presenting problem (PMID:27811305), and in the second missense case
    (PMID:42386221). The first-report authors state the attribution cautiously, as AMMECR1
    possibly playing a role, and that hedge is preserved here.

    How settled is this feature, given that it is in the disease name? Less than the name
    suggests, and the entry now says so with a `REFUTE` item rather than only in prose. The
    first-report authors wrote that the nephrocalcinosis "may be entirely incidental". Two things
    have changed since, and they cut in opposite directions. Against the caveat: their premise
    was that these findings were "unique to our study", and the 2026 second missense case reports
    nephrocalcinosis independently, so the finding is no longer unique. For the caveat: an
    independent recurrence in a second family is a much weaker claim than a mechanism, and none
    has been proposed. The honest position is that the association is now better supported than
    in 2016 and still not established, which is what the two evidence items below record.

    The same "may be entirely incidental" sentence also covers the submucous cleft palate and
    bifid uvula. It is quoted once, here, rather than repeated on the Cleft Palate phenotype -
    which carries a pointer to it in its own `notes:`.
  evidence:
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula."
    explanation: Nephrocalcinosis as the presenting feature in the first AMMECR1 point-mutation family.
  - reference: PMID:42386221
    reference_title: "A Second Report of a Missense Variant in AMMECR1 Causing Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis: Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a patient with a heterozygous de novo AMMECR1 missense variant, NM_015365.3:c.649G>A p.(Val217Met) presenting with clinical features consistent with MFHIEN, including midface hypoplasia, partial hearing impairment, nephrocalcinosis, and elliptocytosis identified on peripheral blood smear."
    explanation: Independent recurrence of nephrocalcinosis with a second missense allele.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Nephrocalcinosis, hypercalciuria, cataracts (in proband II(2)), submucous cleft palate and bifid uvula are unique to our study and may be entirely incidental; we do not have sufficient evidence in support of any causal relationship between AMMECR1 and these manifestations."
    explanation: >-
      The first-report authors declining to attribute the nephrocalcinosis to AMMECR1 at all. It
      refutes the causal claim rather than the observation - the finding is real and repeatedly
      imaged in both half-brothers; what is contested is that AMMECR1 caused it. Recorded because
      nephrocalcinosis is in the disease name, so a reader would otherwise take the association
      as settled. Note the sentence's own premise ("unique to our study") is now superseded by
      the second missense case above.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "We excluded known genetic causes for nephrocalcinosis and idiopathic hypercalciuria in 12 of 14 genes assessed."
    explanation: >-
      A rescued negative result: the alternative monogenic explanations for this patient's renal
      phenotype were looked for and not found, which is what leaves AMMECR1 standing. INDIRECT
      because excluding other causes is not evidence that this gene is the cause. The authors
      qualify it themselves - the two unexcluded genes, PTH and CLDN14, had 45% and 86% coverage
      on the capture kit, and they decline to call them excluded, noting only that neither is on
      the X chromosome.
- name: Short Stature
  category: Growth
  description: >-
    Proportionate short stature, one of the most consistent features across the reported families
    and the observation that motivated the growth-and-bone framing of the disease.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  notes: >-
    No frequency band; see the entry `notes`. Observed in the five-individual loss-of-function
    series (PMID:29193635), the microdeletion pair (PMID:30737907) and the X-linked
    elliptocytosis family, where it is specified as proportionate (PMID:28089922).
  evidence:
  - reference: PMID:29193635
    reference_title: Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They present with short stature, cardiac and skeletal abnormalities, and hearing loss."
    explanation: The core phenotype of the largest reported series.
- name: Developmental Delay and Intellectual Disability
  category: Neurological
  description: >-
    Developmental delay, usually mild intellectual disability, with early speech and language
    delay and infantile hypotonia described in the first point-mutation family. This is the
    "mental retardation" of the 1998 AMME acronym, reassigned from the deletion as a whole to
    AMMECR1.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >-
    No frequency band; see the entry `notes`. Observed in the original AMME family
    (PMID:9598718), the point-mutation half-brothers as speech and language delay
    (PMID:27811305) and the microdeletion pair as mild intellectual disability or
    neurodevelopmental delay (PMID:30737907). The bound term is the developmental-delay term
    rather than the intellectual-disability term because several reports describe delay in young
    children rather than an established cognitive outcome.
  evidence:
  - reference: PMID:30737907
    reference_title: "Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers."
    explanation: Records both the delay and its mildness in two independent deletion patients.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that AMMECR1 is a critical gene in the pathogenesis of AMME, causing midface hypoplasia and elliptocytosis and contributing to early speech and language delay, infantile hypotonia and hearing loss, and may play a role in dysmorphism, nephrocalcinosis and submucous cleft palate."
    explanation: >-
      The authors' graded attribution across features - "causing" for two, "contributing to" for
      three, "may play a role" for three more - which is the source of the hedging used
      throughout this entry.
- name: Abnormal Heart Morphology
  category: Cardiovascular
  description: >-
    Cardiac abnormalities, reported in the five-individual loss-of-function series. They are not
    described in the earlier point-mutation families, so they are curated as part of the spectrum
    rather than as a defining feature.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  notes: >-
    No frequency band; see the entry `notes`. The source describes "cardiac and skeletal
    abnormalities" collectively across five individuals without specifying lesions, so the bound
    term is deliberately the general abnormal-heart-morphology term and nothing narrower is
    claimed.
  evidence:
  - reference: PMID:29193635
    reference_title: Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They present with short stature, cardiac and skeletal abnormalities, and hearing loss."
    explanation: >-
      The only source for cardiac involvement, and the reason the entry claims no specific
      cardiac lesion.
- name: Cleft Palate
  category: Craniofacial
  description: >-
    Midline palatal defects: a submucous cleft palate with bifid uvula in the first
    point-mutation family, and a soft cleft palate in one carrier female.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  notes: >-
    No frequency band; see the entry `notes`. Observed in the point-mutation half-brothers as a
    submucous cleft with bifid uvula (PMID:27811305) and in one carrier female as a soft cleft
    palate (PMID:35084080). The bound term is the general cleft-palate term; `HP:0000176` for a
    submucous cleft would fit the first family but not the carrier, and the entry does not split
    a two-patient observation across two terms.

    The first-report authors' caveat that the submucous cleft palate and bifid uvula "may be
    entirely incidental" applies to this feature as well as to the nephrocalcinosis. It is quoted
    as a `REFUTE` item on the Nephrocalcinosis phenotype and is not repeated here; the carrier
    female's soft cleft palate, reported six years later in an unrelated family, is the
    independent observation that argues against reading it as coincidence.
  evidence:
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We sought to discover a genetic cause for two half-brothers presenting with nephrocalcinosis, early speech and language delay and midface hypoplasia with submucous cleft palate and bifid uvula."
    explanation: The palatal finding in the first AMMECR1 point-mutation family.
  - reference: PMID:35084080
    reference_title: Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All three women reported hearing loss and one was born with a soft cleft palate and hip dysplasia."
    explanation: The same midline defect in a carrier female.
- name: Congenital Hip Dysplasia
  category: Skeletal
  description: >-
    Congenital hip dysplasia, part of the skeletal component of the phenotype and, like the
    palatal defect, reported in a carrier female as well as in affected males.
  phenotype_term:
    preferred_term: Congenital hip dysplasia
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  notes: >-
    No frequency band; see the entry `notes`. The carrier report names hip dysplasia in one of
    three women and states that it had been reported before in male AMMECR1 point-mutation
    carriers. The bound HP term is `Congenital hip dislocation`, which is HPO's label for this
    concept; `preferred_term` keeps the clinical wording used in the source.
  evidence:
  - reference: PMID:35084080
    reference_title: Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, mutations in the AMMECR1 gene have been described in six males with developmental delay, sensorineural hearing loss (SNHL) and/or congenital abnormalities, including fetal nuchal edema, fetal pericardial effusion, talipes, congenital hip dysplasia, elliptocytosis and cleft palate."
    explanation: >-
      Places hip dysplasia among the previously reported male findings, and incidentally lists
      the fetal findings - nuchal edema, pericardial effusion, talipes - that are part of the
      wider spectrum but are not separately curated here.
- name: Hypercalciuria
  category: Renal
  description: >-
    Raised urinary calcium excretion against a persistently normal plasma calcium - so a renal
    calcium-handling problem, not a systemic hypercalcaemia. It is curated because it is the only
    candidate intermediate any source offers between AMMECR1 loss and the nephrocalcinosis in the
    disease name, and because the first-report authors treated it as such: they screened a panel
    of known idiopathic-hypercalciuria and nephrocalcinosis genes before concluding that AMMECR1
    was the remaining candidate.
  phenotype_term:
    preferred_term: Hypercalciuria
    term:
      id: HP:0002150
      label: Hypercalciuria
    temporality: RECURRENT
  notes: >-
    No frequency band; see the entry `notes`. Documented in one individual only - proband II(1)
    of PMID:27811305, where it was repeated and intermittent. It is not reported in his half
    brother II(2), who nonetheless had nephrocalcinosis from infancy, and their carrier mother was
    specifically tested and had no hypercalciuria. `temporality: RECURRENT` follows the source's
    word, "intermittent", rather than describing a sustained abnormality.

    The parenthesis in the "may be entirely incidental" sentence quoted on the Nephrocalcinosis
    phenotype attaches to the cataracts, not to the hypercalciuria - "cataracts (in proband
    II(2))" - so that sentence does not localise the hypercalciuria to either brother. The
    localisation here comes from the case narrative instead.
  evidence:
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "He had repeatedly elevated urine calcium:creatinine ratios, but a persistently normal plasma calcium concentration."
    explanation: >-
      The measurement, in proband II(1), and the normal plasma calcium that makes it a renal
      handling abnormality rather than a systemic one.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "He had persistent nephrocalcinosis with intermittent hypercalciuria."
    explanation: >-
      The same proband at last review aged 11, with both findings persisting and the
      hypercalciuria described as intermittent.
  sequelae:
  - target: Nephrocalcinosis
    description: >-
      A candidate route, not a demonstrated one, and the entry should not be read as claiming
      otherwise. Urinary calcium excess causing parenchymal calcium deposition is ordinary renal
      physiology and is why the first-report authors screened hypercalciuria and nephrocalcinosis
      genes as one panel. But in this family the order of observation runs the wrong way for a
      simple causal story: proband II(1) had nephrocalcinosis on ultrasound in the newborn period
      and his hypercalciuria was documented at age 4, and proband II(2) had nephrocalcinosis from
      infancy with no hypercalciuria reported at all. So the edge records the only intermediate
      the evidence offers, typed with unknown intermediates, and the direct edge from the
      upstream node is deliberately kept in parallel.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Infantile Hypotonia
  category: Neurological
  description: >-
    Low muscle tone from shortly after birth, with poor feeding and delay in gross motor skills.
    The first-report authors list hypotonia among the features AMMECR1 loss contributes to,
    alongside speech and language delay and hearing loss - a stronger attribution than the "may
    play a role" they use for the nephrocalcinosis and cleft palate.
  phenotype_term:
    preferred_term: Infantile hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    onset:
      onset_category: NEONATAL
      notes: >-
        Noted shortly after birth in proband II(1); improved but still present at last review
        aged 11.
  notes: >-
    No frequency band; see the entry `notes`. Present in proband II(1) of PMID:27811305 and
    explicitly absent in his half-brother II(2), who met his motor milestones - one of the
    clearest instances of variable expressivity in this disease, in two boys carrying the same
    allele. The first-report authors also suggest part of it may be secondary to the joint
    hypermobility that persisted through childhood, which is a caveat rather than an alternative
    explanation and is not curated as a separate mechanism.

    Bound to `HP:0001252` (Hypotonia) with the infantile qualifier carried by `preferred_term`
    and the `onset` descriptor, rather than to `HP:0008947`. That term was suggested in review as
    "the infantile form", but its canonical HPO label is `Floppy infant` - a specific severe
    neonatal presentation - and the source describes hypotonia with poor feeding that later
    improved, which is not the same claim. Binding the parent term and qualifying it keeps the
    entry from asserting more than the case narrative does.
  evidence:
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Shortly after birth, proband II(1) was noted to have hypotonia and poor feeding."
    explanation: The onset observation, attributed to the older half-brother.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Proband II(1) had significant infantile hypotonia1 and delay in gross motor skills in addition."
    explanation: >-
      The authors' own summary of the finding in the discussion. The stray "1" is a reference
      marker in the source text and is retained so the quote matches the cache exactly.
genetic:
- name: AMMECR1
  notes: >-
    Encodes a 35.5 kDa nuclear protein of six exons with a ubiquitous transcript, conserved from
    yeast and Caenorhabditis elegans upward, carrying a nucleic-acid-binding RAGNYA fold and
    dimerizing with its paralog AMMECR1L. It was cloned specifically because it lay inside the
    AMME deletion interval and was named after that syndrome; its function was unknown then and
    is still not established.

    The gene's position is the whole story of this disease. It sits telomeric to COL4A5 in Xq22.3,
    inside the interval whose deletion produces AMME. Because COL4A5 accounts for the Alport
    syndrome and nothing else, the remaining features had to belong to a neighbour, and both
    point mutations and AMMECR1-sparing-COL4A5 microdeletions have since confirmed the assignment
    from opposite directions.

    Allelic spectrum: microdeletions (including small ones covering only TMEM164, AMMECR1 and
    SNORD96B), nonsense variants, an X-autosome translocation with inactivation of the normal X,
    and at least two missense alleles - p.G177D and p.Val217Met - both associated with altered
    intranuclear distribution. No genotype-phenotype correlation has been established.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: AMMECR1
    term:
      id: hgnc:467
      label: AMMECR1
  evidence:
  - reference: PMID:10049589
    reference_title: "Identification and characterization of a highly conserved protein absent in the Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E) contiguous gene deletion syndrome (AMME)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Exon 2 of AMMECR1 encodes a domain consisting of six amino acids identically conserved throughout the course of evolution and whose function is as yet unknown."
    explanation: >-
      The deep conservation that made the gene a plausible candidate, together with the statement
      that its function was unknown - which has not since been resolved.
  - reference: PMID:30737907
    reference_title: "Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these cases, AMMECR1 gene appears to be responsible for most of the clinical features of the AMME syndrome except for Alport syndrome."
    explanation: >-
      The gene-disease assignment stated exactly: AMMECR1 carries the AMME phenotype minus its
      renal component.
  - reference: PMID:42386221
    reference_title: "A Second Report of a Missense Variant in AMMECR1 Causing Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis: Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional cases and functional studies are needed to clarify genotype-phenotype correlations and underlying disease mechanisms."
    explanation: >-
      The current state of the gene-disease relationship in its authors' words, and the reason
      this entry asserts no correlation between allele type and phenotype.
prevalence:
- population: Cases reported in the literature worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Roughly a dozen affected males across six reports as of 2026, plus three carrier females. The
    carrier report counts six males with point mutations described previously and ten with a
    deletion including AMMECR1. No population prevalence has been published and none is estimated
    here.
  evidence:
  - reference: PMID:35084080
    reference_title: Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, mutations in the AMMECR1 gene have been described in six males with developmental delay, sensorineural hearing loss (SNHL) and/or congenital abnormalities, including fetal nuchal edema, fetal pericardial effusion, talipes, congenital hip dysplasia, elliptocytosis and cleft palate."
    explanation: The published count of point-mutation males as of that report.
  - reference: PMID:35084080
    reference_title: Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Until now, 10 male patients with a deletion including AMMECR1 have been described"
    explanation: The published count of deletion males as of that report.
diagnosis:
- name: Peripheral blood smear for elliptocytes
  description: >-
    Examination of the blood film is the step most likely to be skipped, and it is the one that
    turns a nonspecific dysmorphic-and-delayed presentation into a recognisable syndrome. The
    most recent case report makes exactly this point: the elliptocytosis was found on smear and
    the authors argue for pairing detailed phenotyping, haematology included, with the genomic
    data. Note the smear can be normal - one of the two point-mutation half-brothers had
    elliptocytes and the other did not.
  diagnosis_term:
    preferred_term: peripheral blood smear examination
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Elliptocytes on the peripheral film, with or without anaemia; a normal smear does not exclude the diagnosis.
  evidence:
  - reference: PMID:42386221
    reference_title: "A Second Report of a Missense Variant in AMMECR1 Causing Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis: Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "emphasize the importance of integrating detailed phenotyping, including hematologic evaluation, with genomic data in the diagnosis of rare multisystem disorders"
    explanation: The authors' explicit diagnostic recommendation, naming haematology.
  notes: >-
    The bound NCIT term is the general Clinical Evaluation term. NCIT's `Blood Smear` term
    (NCIT:C79903) names the specimen rather than a clinical action and is not reachable from
    NCIT:C25218, so it cannot sit in this slot; `preferred_term` carries the specificity instead.
- name: Audiometry
  description: >-
    Hearing loss is sensorineural, mild to moderate where audiograms are reported, and the
    affected frequencies vary between individuals - so a normal impression on casual testing is
    not sufficient, and carriers should be tested too rather than asked.
  diagnosis_term:
    preferred_term: audiometric assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Mild to moderate sensorineural hearing loss with a variable pattern of affected frequencies. A normal audiogram does not exclude the diagnosis and should be repeated.
  evidence:
  - reference: PMID:35084080
    reference_title: Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The audiograms showed mild to moderate SNHL with a variable pattern of the affected frequencies."
    explanation: The audiometric findings, and the basis for the variability caveat.
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "sensorineural hearing loss was first detected at age 3, despite a normal audiogram 1 year previously"
    explanation: >-
      The observation that makes this a surveillance test rather than a one-off one: a normal
      audiogram at age 2 did not exclude the diagnosis in the same child a year later.
  notes: >-
    Longitudinal audiometry, not a single screen. The hearing loss is postnatal in onset and
    progressive - one proband had a normal audiogram at 2 and detectable sensorineural loss at 3,
    and his half-brother's audiogram at 4 had deteriorated from a previous one while still
    reading within the normal range on air conduction. So a normal or borderline result in an
    infant or toddler carries almost no information, and the practical recommendation is repeat
    testing through childhood. Carriers should be tested rather than asked: all three carrier
    females in PMID:35084080 reported hearing loss and had it confirmed audiometrically.
- name: Molecular testing for AMMECR1 variants and Xq22.3 copy number
  description: >-
    Two testing modalities are needed rather than one, because the reported lesions split between
    sequence variants and copy number. Exome sequencing found the point mutations; array-CGH found
    the microdeletions, including small ones covering only TMEM164, AMMECR1 and SNORD96B. A
    sequencing-only workup would miss the deletion patients, and a copy-number-only workup would
    miss the missense ones. Where a deletion is found, its extent relative to COL4A5 is what
    decides whether the patient also has Alport syndrome.
  diagnosis_term:
    preferred_term: molecular analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: A hemizygous AMMECR1 sequence variant, or a deletion involving AMMECR1, with maternal carrier testing where informative.
  evidence:
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing was undertaken on maternal half-siblings."
    explanation: The sequencing route, in the family where the first point mutation was found.
  - reference: PMID:30737907
    reference_title: "Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers."
    explanation: >-
      The copy-number route, and the source for the claim that the deletions can be small enough
      to escape a sequencing-only workup.
treatments:
- name: Hearing aid usage
  description: >-
    Amplification for the sensorineural hearing loss. In the first point-mutation family the
    older half-brother had bilateral mixed hearing loss requiring hearing aids, and the authors
    attribute part of his subsequent speech and language improvement to the correction of his
    hearing and palate together.

    This is phenotype-directed and not disease-modifying, which is the only kind of treatment
    this entity has: nothing is known about what AMMECR1 does, so there is no mechanism to aim
    at. Because the loss is progressive rather than static, the clinical decision is not a
    one-off fitting but repeat audiometry with amplification adjusted as thresholds move - see
    the Audiometry entry under `diagnosis`.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid usage
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  notes: >-
    No `term:` on the treatment_term. NCIT has no clinical-action term for hearing aid usage
    reachable from NCIT:C25218 - the device terms name the equipment and are not clinical actions
    - so this follows the free-text fallback used by the other hearing-aid treatments in this
    knowledge base (Alstrom_Syndrome, ADCA-DN, Apert_Syndrome).

    No `target_mechanisms:`. The schema's own comment on that slot says target names should match
    pathophysiology entry names, and no pathophysiology node in this entry is a thing a hearing
    aid acts on: the mechanism between AMMECR1 loss and the hearing loss is unknown and is typed
    that way throughout. The treatment joins the pathograph through `target_phenotypes` instead,
    which is the honest join point.
  evidence:
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "He had bilateral mixed hearing loss requiring hearing aids"
    explanation: The intervention as reported in proband II(1).
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Both abnormalities were corrected (with hearing aids and cleft palate repair), which may explain the improvement in speech and language development."
    explanation: >-
      The outcome the authors attribute to amplification and palate repair together. INDIRECT
      because it is an uncontrolled single-family observation and the source hedges it - "may
      explain" - and because the two interventions are not separable in it.
- name: Cleft palate repair
  description: >-
    Surgical closure of the submucous cleft palate and bifid uvula. Both point-mutation
    half-brothers had the palatal defect and the older one underwent surgical correction; his
    feeding and gross motor development improved afterwards, and the authors name the repair as
    one of two corrections that may account for his speech and language gains.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cleft palate repair
    term:
      id: NCIT:C168380
      label: Palatorrhaphy
  target_phenotypes:
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  notes: >-
    No `target_mechanisms:`, for the same reason as the hearing aid entry: this acts on the
    malformation, not on any modelled mechanism.
  evidence:
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "He had surgical correction for a submucous cleft palate and bifid uvula."
    explanation: The procedure as reported in proband II(1).
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "He was discharged from physiotherapy, occupational therapy and speech and language therapy before his second birthday, having made improvements in his gross motor development and feeding following cleft palate repair."
    explanation: >-
      The reported outcome. INDIRECT: an uncontrolled observation in one child, with the
      developmental improvement temporally associated with the repair rather than shown to
      follow from it.
- name: Pavlik harness for congenital hip dysplasia
  description: >-
    Abduction bracing for the congenital hip dysplasia, applied in proband II(2). Curated because
    hip dysplasia is one of this entry's phenotypes and this is the only management of it any
    source reports; no outcome is given.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: abduction orthosis (Pavlik harness)
  target_phenotypes:
  - preferred_term: Congenital hip dysplasia
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  notes: >-
    No `term:`. NCIT has no orthosis or bracing clinical-action term reachable from NCIT:C25218,
    and the surgical terms would misdescribe a non-operative treatment, so `preferred_term`
    carries the specificity. The standard hip-dysplasia management this represents is not
    disease-specific and would not be worth an entry on its own; it is here because the source
    reports it in a named patient and because it gives the hip phenotype a join point.
  evidence:
  - reference: PMID:27811305
    reference_title: "AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "He had congenital dysplasia of the hips treated with a Pavlik harness."
    explanation: The intervention as reported in proband II(2).
animal_models:
- name: Zebrafish ammecr1 morphant
  species: Zebrafish
  genotype: knockdown of the zebrafish AMMECR1 orthologue
  publication: PMID:29193635
  description: >-
    The only animal work on this gene in the sources read here. Knocking down the zebrafish
    orthologue produced phenotypes the authors describe as reminiscent of the patients' features -
    which is a similarity claim, not a phenotype-by-phenotype recapitulation, and is treated as
    such below.
  modeled_mechanisms:
  - target: Disturbed Cell-Cycle-Associated Program in Developing Tissues
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Establishes that the gene is required for normal development in a vertebrate, which is the
      main thing this node needs and nearly the only thing the model supplies.
    limitations: >-
      The phenotypes are characterised only as "reminiscent" of the human features, with no
      individual correspondence reported; knockdown is not the same lesion as the human
      microdeletions and point mutations; and no cell-cycle measurement was made in the fish, so
      the model does not test the mechanism this node proposes. Zebrafish also have no midface in
      the sense the human phenotype uses, so the syndrome's defining feature cannot be assessed
      in it at all.
    evidence:
    - reference: PMID:29193635
      reference_title: Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features."
      explanation: >-
        The whole of the reported animal result, quoted at the strength it is stated.
discussions:
- discussion_id: mhen_mechanism_entirely_unknown
  kind: KNOWLEDGE_GAP
  prompt: >-
    What does AMMECR1 actually do in the nucleus, and by what route does losing it produce midface
    hypoplasia, hearing loss, nephrocalcinosis and elliptocytosis?
  attaches_to:
  - pathophysiology#Disturbed Cell-Cycle-Associated Program in Developing Tissues
  rationale: >-
    Twenty-seven years after the syndrome was described and twenty-six after the gene was cloned,
    the function of AMMECR1 is stated in the literature as unknown or, at its strongest, as
    "potentially involved in cell cycle control" on the basis of coexpression. There is no assay
    of AMMECR1 activity, no cell-cycle measurement in patient material, and no proposed route from
    the gene to any one of the four features in the disease name. This is not a gap in one branch
    of an otherwise worked-out mechanism - it is the whole mechanism, and the entry's causal edges
    are typed with unknown intermediates for that reason. The tractable next steps are the
    obvious ones: a conditional mouse or a patient-derived cell model with an actual readout, and
    a molecular function for the RAGNYA fold beyond the sequence prediction.
- discussion_id: mhen_elliptocytosis_not_membrane_defect
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why do the red cells become elliptical when the membrane skeleton is intact?
  attaches_to:
  - pathophysiology#Elliptocytosis Without a Membrane Skeleton Defect
  rationale: >-
    Hereditary elliptocytosis is a disease of the spectrin-actin membrane skeleton, and the
    obvious hypothesis for an inherited elliptocytosis is that the same machinery is affected.
    That hypothesis was tested in the original AMME family and failed: red cell membrane proteins
    were normal and ektacytometry showed normal membrane stability and rigidity. So the
    morphology is produced some other way - plausibly during erythropoiesis rather than in the
    mature cell, given a nuclear protein with a proposed cell-cycle role - and nobody has looked.
    A negative result this clean, left unfollowed for a quarter century, is unusually good value
    for a small experiment.
- discussion_id: mhen_female_carrier_phenotype
  kind: KNOWLEDGE_GAP
  prompt: >-
    How often, and how severely, are female AMMECR1 carriers affected?
  attaches_to:
  - inheritance#X-linked, with a partial phenotype in female carriers
  rationale: >-
    All three carrier females in the one report that examined them had hearing loss, and one had
    a cleft palate and hip dysplasia - and separately, one of the five patients in the
    loss-of-function series is a girl, affected because a balanced X-autosome translocation
    inactivated her normal X. So the "recessive" label is doing less work than it appears to.
    Three women is not a denominator, no other report audiometrically examines carriers, and the
    counselling consequence is direct: a carrier mother currently gets a recurrence risk without
    any statement of her own risk. Resolving it needs systematic audiometry in obligate carriers
    across the reported families, with X-inactivation studies alongside.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Record notes

Identifiers. OMIM #300990 (MFHIEN) and OMIM 300195 (AMMECR1); the parent contiguous-gene syndrome AMME is OMIM 300194. Recorded in prose because the schema's `mappings` block carries `mondo_mappings` only and has no OMIM slot. Relationship to AMME and to Alport syndrome. This entry is the AMMECR1-attributable part of the AMME phenotype, and deliberately not AMME itself. AMME is a contiguous-gene deletion syndrome whose renal component comes from COL4A5; a patient whose deletion removes both genes has Alport syndrome as well, and that belongs to the Alport entries in this KB rather than here. The nephrocalcinosis curated below is a separate finding from Alport nephropathy and is reported in patients whose COL4A5 is intact. Why no phenotype carries a frequency band. The published experience is roughly a dozen affected males spread across six reports, and no two reports ascertain the same way: one is a nephrocalcinosis-led pair of half-brothers, one a growth-and-bone series, one a pair of array-CGH microdeletions, one a family reported for elliptocytosis, one a single missense case. There is no cohort and therefore no denominator, so every phenotype below records which reports observed it in `notes` instead of carrying a manufactured band. Assigning bands across incommensurable case reports would produce numbers that look like frequencies and are not. Evidence base. Six PMIDs: the founding contiguous-gene description (PMID:9598718), the cloning of AMMECR1 out of the deleted interval (PMID:10049589), the first point mutation with functional work (PMID:27811305), a second family reported as X-linked elliptocytosis with impaired growth (PMID:28089922), the five-individual loss-of-function series with the zebrafish knockdown (PMID:29193635), two AMMECR1-only microdeletions (PMID:30737907), the female-carrier report with fetal cochlear immunohistochemistry (PMID:35084080), and the second missense case (PMID:42386221). A corrigendum to PMID:28089922 was published as PMID:29174631. It has no fetchable abstract, so nothing is cited from it and no claim here rests on it; it is named so a reader checking that paper knows the correction exists. What is not asserted. No mechanism is claimed between AMMECR1 loss and any individual phenotype: the causal edges below are typed as having unknown intermediates and say so in their descriptions. No genotype-phenotype correlation is asserted - the most recent report states that additional cases and functional studies are needed to establish one. Treatments. An earlier draft of this entry carried no `treatments:` block and said no source described an intervention. That was wrong and is corrected here: the first point-mutation report describes hearing aids and submucous cleft palate repair in proband II(1), with a reported outcome, and those are now curated. What remains true is the reason the block looked unnecessary - there is no disease-modifying treatment and there cannot yet be one, because the gene's function is unknown. Both entries are phenotype-directed, both join the pathograph through `target_phenotypes` rather than `target_mechanisms`, and none should be read as acting on a mechanism. One intervention in the source is deliberately not curated: the bilateral percutaneous achilles tenotomies proband II(1) had at two months, because the talipes they treated is not curated as a phenotype in this entry - it appears only inside a quoted list of previously reported findings. Deep research. A Falcon deep-research report is committed alongside this entry. It passed `just preflight-dr` against MONDO:0010516 with AMMECR1 mentioned 41 times, the correct OMIM number recovered independently, and COL4A5 a distant second at 9 - which for this disease is the right shape, since COL4A5 is the neighbouring gene the entity had to be separated from. Reference validation resolved 4 of 4 citations with a confabulation rate of 0, and term validation resolved 29 of 30 with none unresolved. The report was used as a lead source only - every snippet below is anchored to a PMID fetched into `references_cache/` and read directly.

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Disease Characteristics Research Template
Edison Scientific Literature 15 citations 2026-09-04T14:18:01.890513

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Midface Hypoplasia, Hearing Impairment, Elliptocytosis, and Nephrocalcinosis covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Research report: AMMECR1-related midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis

Executive summary

Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MFHEIN; OMIM 300990) is an ultra-rare X-linked Mendelian disorder caused by germline disruption of AMMECR1 at Xq23. The best-established manifestations are midface hypoplasia/dysmorphism, developmental or speech delay, hypotonia, short stature or growth failure, sensorineural hearing loss (SNHL), skeletal abnormalities, and variably penetrant elliptocytosis. Nephrocalcinosis, hypercalciuria, cleft palate, congenital heart defects, hip dysplasia, and other congenital anomalies occur in some patients, but the very small literature prevents reliable frequencies and makes causality less certain for several findings. AMMECR1-related MFHEIN must be distinguished from the larger Xq22.3–q23 AMME contiguous-gene deletion syndrome, in which deletion of COL4A5 causes Alport nephropathy and associated ocular/auditory disease. (andreoletti2017ammecr1asingle pages 1-1, moysesoliveira2018inactivationofammecr1 pages 2-3, andreoletti2017ammecr1asingle pages 5-6)

The foundational primary reports are Andreoletti et al., Journal of Medical Genetics 2017, DOI 10.1136/jmedgenet-2016-104100; Moysés-Oliveira et al., Human Mutation 2018, DOI 10.1002/humu.23373; Poreau et al., American Journal of Medical Genetics A 2019, DOI 10.1002/ajmg.a.61057; and Koene et al., American Journal of Medical Genetics A 2022, DOI 10.1002/ajmg.a.62669. No disease-specific 2023–2024 mechanistic study, natural-history cohort, guideline, or interventional trial was identified. Consequently, this report avoids presenting case-series proportions as population frequencies.

The following table provides a compact knowledge-base representation.

Domain Best-supported finding Evidence strength/type Suggested ontology terms
Disease identity Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MFHEIN; OMIM 300990) is an ultra-rare, multisystem AMMECR1-related disorder distinct from the broader COL4A5-containing AMME contiguous-gene deletion syndrome. Strong disease-level evidence from multiple human case series; boundaries remain evolving because very few patients are known. (andreoletti2017ammecr1asingle pages 1-1, moysesoliveira2018inactivationofammecr1 pages 2-3, poreau2019xq22.3q23microdeletionharboring pages 4-5) MONDO: AMMECR1-related MFHEIN; HP: phenotypic abnormality
Cause and inheritance Hemizygous missense or loss-of-function variants and intragenic/whole-gene deletions affecting AMMECR1 cause an X-linked disorder. Affected males usually have the fuller phenotype; heterozygous females can manifest features depending partly on X-inactivation. Strong human genetic segregation plus functional evidence; variable expressivity demonstrated. (moysesoliveira2018inactivationofammecr1 pages 1-2, koene2022hearinglosscleft pages 1-3, andreoletti2017ammecr1asingle pages 3-4) X-linked inheritance (HP:0010985); AMMECR1; germline variant
Core phenotypes Recurrent findings include midface hypoplasia, short stature or growth failure, developmental/speech delay, sensorineural hearing loss, and subtle or overt elliptocytosis. Moderate evidence from small human series; no reliable population-level frequencies. Elliptocytosis is variably penetrant and can be absent on an early smear. (moysesoliveira2018inactivationofammecr1 pages 4-6, andreoletti2017ammecr1asingle pages 6-7, poreau2019xq22.3q23microdeletionharboring pages 4-5) Midface hypoplasia (HP:0011800); short stature (HP:0004322); global developmental delay (HP:0001263); speech delay (HP:0000750); sensorineural hearing impairment (HP:0000407); elliptocytosis (HP:0004445)
Associated phenotypes Nephrocalcinosis/hypercalciuria, hypotonia, cleft or submucous cleft palate with bifid uvula, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, cardiac defects, genital anomalies, talipes, ocular findings, and fetal edema have been reported. Some may be uncommon, incidental, or attributable to neighboring genes in larger deletions. Limited human case evidence; causality is strongest for growth, skeletal, cardiac, palate, and hearing phenotypes but less secure for nephrocalcinosis and some ocular findings. (moysesoliveira2018inactivationofammecr1 pages 4-6, andreoletti2017ammecr1asingle pages 7-8, andreoletti2017ammecr1asingle pages 8-8) Nephrocalcinosis (HP:0000121); hypercalciuria (HP:0002150); muscular hypotonia (HP:0001252); cleft palate (HP:0000175); bifid uvula (HP:0000193); joint hypermobility (HP:0001382); talipes equinovarus (HP:0001762)
Temporal course Congenital findings may be detectable prenatally or neonatally; hypotonia, feeding problems, skeletal/palatal anomalies, and dysmorphism occur early. Hearing loss and elliptocytosis may emerge or worsen during childhood, while speech development and facial appearance can improve with age and intervention. Longitudinal observations from individual patients, not a formal natural-history cohort. (andreoletti2017ammecr1asingle pages 1-2, andreoletti2017ammecr1asingle pages 6-7, andreoletti2017ammecr1asingle pages 3-3, andreoletti2017ammecr1asingle pages 5-6) Congenital onset (HP:0003577); infantile onset (HP:0003593); childhood onset (HP:0011463); progressive hearing impairment (HP:0001730)
Female carriers Three related heterozygous females with an exon-4 deletion all reported mild-to-moderate SNHL; one also had soft-palate cleft and congenital hip dysplasia. Peripheral-blood X-inactivation ranged from 60:40 to 90:10, suggesting—but not proving—a severity relationship. Direct human pedigree, audiometric, deletion, and X-inactivation evidence; penetrance cannot be generalized from one family. (koene2022hearinglosscleft pages 4-5, koene2022hearinglosscleft pages 1-3, koene2022hearinglosscleft pages 3-4) Female limited expression; skewed X-inactivation; sensorineural hearing impairment (HP:0000407); cleft soft palate (HP:0000185); congenital hip dislocation/dysplasia
Diagnostics Phenotype-led evaluation should include sequencing and deletion/duplication analysis of AMMECR1, peripheral blood smear, audiology, renal ultrasound plus renal function/calcium studies, developmental and palatal assessment, growth/skeletal examination, and consideration of cardiac and ophthalmic assessment. WES identified the original missense family; CMA detects regional deletions; WGS may help when sequencing and copy-number tests are unrevealing. WES, Sanger segregation, blood-smear, audiometric, ultrasound, and microarray approaches are documented in cases; no consensus diagnostic criteria or validated biomarker exists. (andreoletti2017ammecr1asingle pages 1-2, andreoletti2017ammecr1asingle pages 3-4, andreoletti2017ammecr1asingle pages 7-8, andreoletti2017ammecr1asingle pages 4-5) Genetic testing; peripheral blood smear; pure-tone audiometry; renal ultrasonography; developmental assessment
Key differential Exclude Xq22.3–q23 contiguous deletions involving COL4A5, which add Alport nephropathy/hematuria and related ocular manifestations. Other hearing-loss-plus-nephrocalcinosis disorders and hereditary red-cell membrane disorders should be considered according to biochemical findings. Direct genotype–phenotype comparison supports the COL4A5 distinction; broader differential is clinical inference. (andreoletti2017ammecr1asingle pages 1-2, andreoletti2017ammecr1asingle pages 5-6, andreoletti2017ammecr1asingle pages 6-7) Alport syndrome; hematuria (HP:0000790); distal renal tubular acidosis; hereditary elliptocytosis
Management No disease-modifying therapy is established. Reported real-world care includes hearing aids, cleft-palate repair, developmental/speech support, surveillance of renal, growth, skeletal, and cardiac abnormalities, and individualized treatment of complications. Growth-hormone response was reported in one short-stature patient but is not validated as syndrome-specific therapy. Case-level treatment evidence only; no controlled treatment studies. Hearing and palate treatment was followed by improved speech/language in affected children. (moysesoliveira2018inactivationofammecr1 pages 4-6, koene2022hearinglosscleft pages 1-3, andreoletti2017ammecr1asingle pages 6-6) Hearing aid; palatoplasty; speech therapy; developmental intervention; genetic counseling; growth-hormone therapy
Cellular mechanism AMMECR1 is a nuclear protein containing two RAGNYA folds. The p.Gly177Asp protein showed abnormal, nonuniform nuclear localization and fewer transfected GFP-positive cells, consistent with protein dysfunction or instability. AMMECR1 loss was associated with increased AMMECR1L expression, possibly providing partial compensation. Nuclear localization and mutant mislocalization demonstrated in cultured cells; instability and AMMECR1L compensation remain inferred rather than proven. (andreoletti2017ammecr1asingle pages 8-9, andreoletti2017ammecr1asingle pages 4-5, moysesoliveira2018inactivationofammecr1 pages 6-8) GO: nucleus (GO:0005634); protein localization to nucleus; protein stability; nucleic-acid binding; CL: cultured human epithelial cell
Molecular pathway RAGNYA-fold structure predicts nucleic-acid interaction and possibly an RNA-associated catalytic role; coexpression with cell-cycle genes suggests a developmental growth mechanism. No specific Wnt, MAPK, mTOR, PI3K–AKT, immune, metabolic, or epigenetic pathway has been causally demonstrated. Structural/computational prediction and coexpression evidence; biochemical substrate and downstream pathway remain unknown. (moysesoliveira2018inactivationofammecr1 pages 1-2, moysesoliveira2018inactivationofammecr1 pages 6-8) GO: nucleic acid binding; cell-cycle regulation; developmental growth; RNA modification—provisional only
Affected tissues/cells Clinical evidence implicates craniofacial mesenchyme/palate, inner ear, erythrocytes, growth plate/bone, kidney, heart, and nervous/developmental systems. AMMECR1 protein expression was demonstrated in developing human fetal cochlear epithelium at gestational weeks 13 and 17. Multisystem human phenotype plus direct fetal-inner-ear immunohistochemistry; disease-critical cell populations are otherwise undefined. (koene2022hearinglosscleft pages 4-5, koene2022hearinglosscleft pages 1-3, andreoletti2017ammecr1asingle pages 7-8) CL: erythrocyte (CL:0000232); epithelial cell (CL:0000066); chondrocyte (CL:0000138); UBERON: inner ear, kidney, midface, palate, bone, heart
Model organisms Zebrafish ammecr1 knockdown altered approximately 90% of transcripts and generated patient-reminiscent developmental phenotypes. Mouse and human proteins share approximately 95.2% amino-acid identity, supporting evolutionary conservation, but no disease-specific mammalian knockout phenotype is established in the cited evidence. Functional zebrafish knockdown plus comparative mouse-ortholog evidence; morpholino limitations apply and complete human MFHEIN recapitulation is unproven. (moysesoliveira2018inactivationofammecr1 pages 1-2, moysesoliveira2018inactivationofammecr1 pages 6-8) Danio rerio (NCBITaxon:7955); Mus musculus (NCBITaxon:10090); gene knockdown; developmental abnormality
Epidemiology and evidence gaps Prevalence, incidence, carrier frequency, sex ratio, survival, quality-of-life scores, penetrance, and prognostic biomarkers are unknown. Published evidence consists of a handful of families and deletion cases, precluding meaningful percentages. Very low-certainty epidemiology; absence of registries and natural-history cohorts. (andreoletti2017ammecr1asingle pages 1-1, moysesoliveira2018inactivationofammecr1 pages 1-2, koene2022hearinglosscleft pages 1-3) Rare disease; ultra-rare genetic disease; natural-history study needed
Trials and advanced therapies No AMMECR1/MFHEIN-specific interventional trial, gene therapy, RNA therapy, cell therapy, targeted drug, or validated pharmacogenomic strategy was identified. Clinical-trial search negative; current care is supportive and complication-directed. Supportive care; symptom management; no applicable investigational intervention term

Table: Concise knowledge-base summary separating well-supported human and functional findings from hypotheses and evidence gaps. Ontology suggestions emphasize established terms while avoiding unsupported precision.

1. Disease information

Definition and nomenclature

MFHEIN is an AMMECR1-related, multisystem developmental disorder. Synonyms include MFHEIN, AMMECR1-related disorder, and, less precisely, AMMECR1-related AMME phenotype. The historical acronym AMME means Alport syndrome, intellectual disability/mental retardation, midface hypoplasia, and elliptocytosis and ordinarily refers to a larger Xq22.3–q23 contiguous deletion; it should not be used without qualification for isolated AMMECR1 disease. (andreoletti2017ammecr1asingle pages 1-1, andreoletti2017ammecr1asingle pages 6-7)

Identifiers: OMIM phenotype 300990 is supported by the literature. A dedicated MONDO identifier, Orphanet number, MeSH heading, and disease-specific ICD-10/ICD-11 code were not established in the retrieved authoritative sources. Practical coding therefore generally requires phenotype or congenital-anomaly codes rather than a unique MFHEIN code. Suggested knowledge-base label: “AMMECR1-related midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis.”

The evidence is aggregated disease-level literature derived from individual patients and families, not EHR-scale cohorts, registries, or population surveillance. The original single-gene report described two maternal half-brothers; later work added a small number of loss-of-function cases, deletion cases, and manifesting female relatives. (andreoletti2017ammecr1asingle pages 1-1, moysesoliveira2018inactivationofammecr1 pages 1-2, koene2022hearinglosscleft pages 1-3)

Direct abstract statements

Andreoletti et al. concluded that a single missense mutation “causes a phenotype of midface hypoplasia, mild intellectual disability and the presence of elliptocytes” and that AMMECR1 contributes to speech/language delay, hypotonia, and hearing loss. (andreoletti2017ammecr1asingle pages 1-1)

Koene et al. reported that “all three women reported hearing loss” and that audiograms showed “mild to moderate SNHL with a variable pattern of the affected frequencies.” (koene2022hearinglosscleft pages 1-3)

2. Etiology, risk, and protective factors

Causal factors

The initiating cause is a germline AMMECR1 variant that reduces or alters gene function. Documented lesions include:

  • Hemizygous missense c.530G>A, p.(Gly177Asp) in two maternal half-brothers, inherited from their heterozygous mother. It was absent from ExAC, dbSNP, and local controls at the time and altered nuclear distribution in transfected cells. (andreoletti2017ammecr1asingle pages 3-4, andreoletti2017ammecr1asingle pages 4-5)
  • Nonsense variants p.(Arg168Ter), maternally inherited, and p.(Tyr143Ter), de novo. (moysesoliveira2018inactivationofammecr1 pages 4-6)
  • A reported c.133C>T, p.(Arg45Ter) allele in comparative case material. (poreau2019xq22.3q23microdeletionharboring pages 4-4)
  • Intragenic deletion of approximately 23 kb containing exon 4 in a family with affected females. (koene2022hearinglosscleft pages 1-3, koene2022hearinglosscleft pages 3-4)
  • Whole-gene or multigene deletions and an X-autosome translocation interrupting AMMECR1; in the affected female with the translocation, the normal X was preferentially inactivated. (moysesoliveira2018inactivationofammecr1 pages 1-2, moysesoliveira2018inactivationofammecr1 pages 2-3)

These are constitutional variants. No somatic disease mechanism is known. Public-database ACMG classifications and current gnomAD allele counts could not be verified from the retrieved texts; the original p.Gly177Asp report called it a VUS before segregation and functional evidence supported pathogenicity. Variant interpretation should therefore be performed against current ClinVar/gnomAD data rather than copying the historical label.

Risk factors and modifiers

The principal risk factor is inheritance of a familial AMMECR1 variant. Hemizygous males generally have greater risk of a multisystem phenotype. Heterozygous females can be symptomatic: in one family all three carriers had SNHL, and peripheral-blood X-inactivation ratios were 90:10, 80:20, and 60:40. Skewing may modify severity but was not proven causal and blood may not reflect disease-relevant tissues. (koene2022hearinglosscleft pages 4-5, koene2022hearinglosscleft pages 1-3)

AMMECR1L is a plausible molecular modifier: its RNA and protein abundance increased in AMMECR1-deficient patient cells, suggesting partial compensation, but no human modifier allele has been demonstrated. (moysesoliveira2018inactivationofammecr1 pages 6-8, moysesoliveira2018inactivationofammecr1 pages 1-2)

No environmental, infectious, lifestyle, occupational, age-related susceptibility, or protective factor is known to cause MFHEIN. No protective allele, diet, supplement, or exposure has been validated. Environmental influences may modify general renal-stone or hearing risk, but that is not established as an AMMECR1 gene–environment interaction.

3. Phenotypes

Because published patients number only in the low double digits across heterogeneous variant classes, population frequencies cannot be calculated. “Recurrent,” “reported,” and “uncertain” below are more defensible than percentages.

  • Midface hypoplasia and facial dysmorphism — congenital physical sign; recurrent and sometimes less conspicuous with age. Associated features include thin upper lip, long philtrum, small or pointed jaw, broad nasal tip, abnormal palpebral fissures, and short neck. Suggested HPO: Midface hypoplasia HP:0011800, Micrognathia HP:0000347. (andreoletti2017ammecr1asingle pages 6-6, poreau2019xq22.3q23microdeletionharboring pages 4-5)
  • SNHL — clinical/functional sign; may begin in childhood and progress. One patient’s loss began at age three. Female carriers had mild-to-moderate, flat, low-frequency, or high-frequency patterns; fetal cochlear expression supports biological plausibility. HPO: Sensorineural hearing impairment HP:0000407, Progressive hearing impairment HP:0001730. Hearing affects communication, schooling, and speech development. (koene2022hearinglosscleft pages 4-5, koene2022hearinglosscleft pages 1-3, andreoletti2017ammecr1asingle pages 5-6)
  • Elliptocytosis — laboratory/morphologic abnormality, usually mild. Scattered elliptocytes and anisocytosis persisted on repeat smear in one older brother, whereas his younger affected brother had a normal smear at four years. This supports variable or age-related expression and means a normal smear does not exclude MFHEIN. HPO: Elliptocytosis HP:0004445. Clinically significant hemolysis has not been established. (andreoletti2017ammecr1asingle pages 6-7, andreoletti2017ammecr1asingle pages 3-4)
  • Nephrocalcinosis/hypercalciuria — imaging/laboratory finding in the original family and selected tabulated cases; causality is less secure than the acronym implies. HPO: Nephrocalcinosis HP:0000121, Hypercalciuria HP:0002150. Long-term CKD risk specifically attributable to MFHEIN is unknown. (andreoletti2017ammecr1asingle pages 7-8, andreoletti2017ammecr1asingle pages 8-8)
  • Developmental, speech, and language delay — pediatric neurodevelopmental phenotype, usually mild to variable. Some improvement/catch-up occurred: at age five one child attended mainstream school with better speech/language. Hearing loss and cleft palate may contribute. HPO: Global developmental delay HP:0001263; Delayed speech and language development HP:0000750. (andreoletti2017ammecr1asingle pages 3-3, andreoletti2017ammecr1asingle pages 6-6)
  • Hypotonia and motor delay — congenital/infantile sign; may coexist with hypermobility. HPO: Muscular hypotonia HP:0001252; Delayed gross motor development HP:0002194. (andreoletti2017ammecr1asingle pages 1-2, andreoletti2017ammecr1asingle pages 7-8)
  • Growth and skeletal disease — short stature/failure to thrive, delayed bone age, osteopenia/demineralization, scoliosis, radioulnar synostosis, wormian bones, Looser zones, cone-shaped phalanges, talipes, and hip dysplasia have been reported. Severity is variable. HPO: Short stature HP:0004322, Osteopenia HP:0000938, Scoliosis HP:0002650, Talipes equinovarus HP:0001762. (moysesoliveira2018inactivationofammecr1 pages 4-6, andreoletti2017ammecr1asingle pages 1-2)
  • Palatal/midline abnormalities — cleft or submucous cleft palate and bifid uvula, congenital and surgically actionable. HPO: Cleft palate HP:0000175; Bifid uvula HP:0000193. These can impair feeding, speech, and middle-ear function. (andreoletti2017ammecr1asingle pages 1-1, andreoletti2017ammecr1asingle pages 6-6)
  • Cardiac findings — atrial septal defect, arrhythmia/tachycardia, patent ductus arteriosus, right bundle-branch block, and mild tricuspid regurgitation occur in individual cases. HPO terms should be assigned per lesion rather than treating “heart disease” as obligatory. (moysesoliveira2018inactivationofammecr1 pages 4-6, andreoletti2017ammecr1asingle pages 7-8)
  • Other reported findings — fetal nuchal edema/pericardial effusion, poor feeding, joint hypermobility, clinodactyly, genital anomalies, ureterocele/reflux, strabismus, cataract, myopia, and dental abnormalities. Several may be private, incidental, or deletion-size dependent. (andreoletti2017ammecr1asingle pages 1-2, moysesoliveira2018inactivationofammecr1 pages 4-6, andreoletti2017ammecr1asingle pages 8-8)

No validated EQ-5D, SF-36, PROMIS, behavioral, psychiatric, or disease-specific quality-of-life data exist. The probable major burdens are hearing/communication impairment, developmental support needs, repeated specialist surveillance, palate surgery, and skeletal or renal morbidity.

4. Genetic and molecular information

Causal gene: AMMECR1, Xq23, encoding an approximately 33-kDa nuclear protein with two RAGNYA folds. The retrieved literature used transcript NM_015365.2. The protein’s physiological substrate and catalytic activity remain unknown. (koene2022hearinglosscleft pages 3-4, moysesoliveira2018inactivationofammecr1 pages 6-8)

The combined human evidence supports loss of function as a major disease mechanism: nonsense alleles, intragenic/whole-gene deletions, and a gene-disrupting translocation all cause overlapping phenotypes. The p.Gly177Asp missense protein retains nuclear localization but has an abnormal nonuniform pattern and fewer GFP-positive transfected cells, consistent with altered localization, instability, or degradation. The latter two mechanisms are interpretations rather than directly quantified biochemical conclusions. (andreoletti2017ammecr1asingle pages 8-9, andreoletti2017ammecr1asingle pages 4-5)

No recurrent founder allele, pathogenic repeat expansion, mitochondrial variant, aneuploidy, inversion, somatic mosaicism, or validated epigenetic signature is known. Larger Xq22.3–q23 deletions can include TMEM164, RGAG1, ACSL4, COL4A5, and other genes; phenotypes in these patients cannot automatically be assigned solely to AMMECR1. In particular, COL4A5 deletion explains Alport nephropathy, while ACSL4 has been proposed to contribute substantially to intellectual disability in the broader deletion syndrome. (andreoletti2017ammecr1asingle pages 6-7, andreoletti2017ammecr1asingle pages 6-6)

5. Environmental information

There is no evidence that toxins, radiation, pollution, occupation, smoking, alcohol, diet, exercise, or infectious agents initiate MFHEIN. It is not infectious or zoonotic. General avoidance of excessive noise and nephrotoxic exposures may be clinically sensible in a patient with hearing or renal vulnerability, but these are precautionary principles—not demonstrated disease-specific protective factors.

6. Mechanism and pathophysiology

Ordered causal chain

  1. A germline AMMECR1 missense, truncating, deletion, or gene-disrupting rearrangement leads to absent, reduced, or abnormally localized AMMECR1 protein. (moysesoliveira2018inactivationofammecr1 pages 1-2, andreoletti2017ammecr1asingle pages 4-5)
  2. AMMECR1 dysfunction leads to impaired nuclear AMMECR1 activity; its two RAGNYA folds suggest nucleic-acid interaction, but the substrate and enzymatic function are inferred, not demonstrated. (moysesoliveira2018inactivationofammecr1 pages 6-8)
  3. Impaired nuclear activity is inferred to disrupt developmental transcription/RNA handling or cell-cycle-linked programs; this is supported by coexpression with cell-cycle genes, not by a proven signaling pathway. (moysesoliveira2018inactivationofammecr1 pages 1-2)
  4. These developmental disturbances lead to, or are inferred to lead to, tissue-specific defects in craniofacial/palatal development, growth plate and skeletal development, heart development, neurodevelopment, and fetal cochlear epithelium. Zebrafish knockdown producing patient-like developmental phenotypes supports this broad developmental role. (moysesoliveira2018inactivationofammecr1 pages 1-2)
  5. Craniofacial branch: altered embryonic craniofacial development results in midface hypoplasia, dysmorphism, cleft/submucous palate, and bifid uvula. The intermediate cell biology is inferred.
  6. Auditory branch: altered development or maintenance of AMMECR1-expressing cochlear epithelial cells results in SNHL; fetal-inner-ear expression is demonstrated, whereas the exact affected cochlear cell and lesion are unknown. (koene2022hearinglosscleft pages 4-5)
  7. Erythroid branch: AMMECR1 dysfunction results in variably penetrant elliptocyte morphology, but the link to the erythrocyte membrane/cytoskeleton is unknown and no hemolytic mechanism has been demonstrated. (andreoletti2017ammecr1asingle pages 3-4)
  8. Renal branch: an unresolved developmental or tubular mechanism may lead to hypercalciuria and nephrocalcinosis; causality is weaker and alternative renal genetic causes should be excluded. (andreoletti2017ammecr1asingle pages 8-8)
  9. Increased AMMECR1L expression may partially compensate for AMMECR1 loss, contributing to variable severity; this is inferred from patient-cell expression rather than clinical modifier genetics. (moysesoliveira2018inactivationofammecr1 pages 6-8)

No causal Wnt, MAPK, mTOR, PI3K–AKT, autophagy, apoptosis, inflammatory, immune, oxidative-stress, or specific metabolic pathway has been established. Likewise, no disease-specific transcriptomic, proteomic, metabolomic, lipidomic, methylomic, single-cell, spatial-transcriptomic, organoid, iPSC, or CRISPR-screen signature has been reported.

Suggested provisional GO annotations are nucleus (GO:0005634), nucleic-acid binding, protein localization to nucleus, regulation of cell cycle, developmental growth, skeletal-system development, heart development, and inner-ear development. “RNA modification” should be marked computationally predicted, not curated as a demonstrated MFHEIN mechanism. Suggested CL terms include erythrocyte CL:0000232, epithelial cell CL:0000066, and chondrocyte CL:0000138; only fetal cochlear epithelial expression is directly supported at cell-type level.

7. Anatomical structures affected

Primary implicated sites are the midface and palate, inner ear/cochlea, blood/erythrocytes, kidney, skeleton/growth plate, heart, and developing nervous system. Secondary sites can include eye, urinary tract, joints, and genital tract. Cochlear immunohistochemistry demonstrated AMMECR1 expression at gestational weeks 13 and 17, evolving from broad epithelial expression to selected apical cells. (koene2022hearinglosscleft pages 4-5)

Suggested UBERON concepts: midface, palate, inner ear/cochlea, kidney, blood, bone, growth plate, heart, and central nervous system. Subcellular localization is principally the nucleus (GO:0005634), although overexpressed tagged protein was also detected in cytoplasmic fractions. (moysesoliveira2018inactivationofammecr1 pages 6-8)

Hearing loss may be symmetric or asymmetric; other disease manifestations have no established lateralization pattern. Talipes can be bilateral. (andreoletti2017ammecr1asingle pages 1-2, koene2022hearinglosscleft pages 1-3)

8. Temporal development and natural history

Onset is congenital/developmental. Fetal nuchal edema, pericardial effusion, short femurs, talipes, and structural anomalies can be prenatal; hypotonia, feeding difficulty, dysmorphism, cleft palate, and growth problems may be neonatal or infantile. (andreoletti2017ammecr1asingle pages 1-2)

Hearing loss can become evident in early childhood and may progress. Elliptocytosis may be detectable in infancy but can also be absent at age four and present by age ten. Facial dysmorphism can become less apparent, and some children show developmental and speech catch-up after treatment of hearing and palate problems. (andreoletti2017ammecr1asingle pages 6-7, andreoletti2017ammecr1asingle pages 3-3, andreoletti2017ammecr1asingle pages 7-8)

No validated disease stages, remission pattern, progression rate, or critical treatment window exists. The condition is genetically lifelong, but individual manifestations may be stable, progressive, or developmentally ameliorating. Early childhood is a practical intervention window for hearing, palate, feeding, and developmental support.

9. Inheritance and population

Inheritance is X-linked, usually described as X-linked recessive but with manifesting heterozygous females. Both maternally inherited and de novo variants occur. X-inactivation contributes to female expression, but penetrance is unknown. Variable expressivity is clear in males and females. (koene2022hearinglosscleft pages 4-5, moysesoliveira2018inactivationofammecr1 pages 1-2, andreoletti2017ammecr1asingle pages 3-4)

No evidence supports anticipation. Germline mosaicism remains theoretically possible after an apparently de novo variant but has not been documented. No founder effect, consanguinity association, carrier frequency, ethnic enrichment, geographic concentration, sex ratio, prevalence, or incidence estimate is available. The literature comprises a handful of families, so an estimate per 100,000 would be misleading.

Standard counseling for a heterozygous mother is a 50% transmission probability per pregnancy; sons inheriting the variant are hemizygous, while daughters inheriting it may be asymptomatic or variably affected. Counseling must account for uncertain female penetrance.

10. Diagnostics

There are no formal diagnostic criteria. A phenotype-led workup should include:

  1. Molecular testing: sequencing plus deletion/duplication analysis of AMMECR1. WES identified the original missense family, with Sanger confirmation and segregation. Exome/genome analysis should include CNV calling. CMA is appropriate where multiple congenital anomalies or a regional Xq deletion is suspected; WGS can detect coding, copy-number, structural, and some deep-intronic lesions when earlier tests are negative. (andreoletti2017ammecr1asingle pages 1-2, andreoletti2017ammecr1asingle pages 3-4)
  2. Define deletion extent: determine whether COL4A5, ACSL4, or other neighboring genes are involved, because this materially changes renal, ocular, and neurodevelopmental interpretation.
  3. Hematology: complete blood count, reticulocytes/hemolysis studies if indicated, and expert peripheral smear. Mild scattered elliptocytes may be missed, and a normal smear does not exclude disease. (andreoletti2017ammecr1asingle pages 3-4, andreoletti2017ammecr1asingle pages 6-7)
  4. Audiology: newborn screen review, age-appropriate pure-tone or objective audiometry, tympanometry, and longitudinal monitoring because SNHL can be progressive.
  5. Renal evaluation: urinalysis for blood/protein, serum creatinine/electrolytes/bicarbonate/calcium/phosphate, urine calcium and citrate as clinically appropriate, blood pressure, and renal ultrasound for nephrocalcinosis or structural abnormalities.
  6. Development and anatomy: developmental, speech/language, feeding, palate/velopharyngeal, growth, skeletal, joint, cardiac, ophthalmic, and genital/urinary assessments tailored to findings. The broad reported phenotype supports this baseline multisystem evaluation. (andreoletti2017ammecr1asingle pages 7-8)

Differential diagnosis: COL4A5-containing AMME deletion/Alport syndrome is distinguished by hematuria and progressive glomerular nephropathy; exome sequencing may miss deep-intronic COL4A5 variants. (andreoletti2017ammecr1asingle pages 5-6) Other important phenotype-driven alternatives include hereditary elliptocytosis due to erythrocyte-membrane genes; SLC4A1-related distal renal tubular acidosis with red-cell abnormalities; ATP6V1B1/ATP6V0A4-related distal RTA with SNHL and nephrocalcinosis; branchio-oto-renal disorders; and other syndromic cleft-palate/short-stature conditions. These broader alternatives are clinical differentials rather than documented AMMECR1 phenocopies.

There is no newborn population screen, biochemical biomarker, enzyme assay, biopsy criterion, or validated omics diagnostic. Cascade testing is appropriate after a familial pathogenic/likely pathogenic variant is established.

11. Outcome and prognosis

No survival curve, mortality rate, life-expectancy estimate, standardized disability score, or prognostic biomarker exists. The reported phenotype is generally compatible with childhood survival and, in some patients, normal intelligence and mainstream schooling. One child showed developmental improvement by age five, and facial features may soften over time. (andreoletti2017ammecr1asingle pages 3-3)

Likely morbidity arises from progressive hearing loss, communication delay, cleft-palate complications, growth/skeletal abnormalities, congenital heart disease, and possible renal calcification. Elliptocytosis is often subtle and has not been shown to produce consistent hemolytic anemia. Prognosis should be individualized according to renal function, hearing trajectory, cardiac lesion, skeletal disease, and deletion extent.

12. Treatment and current applications

There is no disease-modifying pharmacotherapy and no established genotype-specific drug, pharmacogenomic rule, gene therapy, RNA therapy, cell therapy, or immunotherapy.

Real-world management is multidisciplinary and complication directed:

  • Hearing: hearing aids were used in reported patients; cochlear implantation would follow ordinary audiological criteria, although no MFHEIN-specific outcome is published. Suggested NCIT concepts: Hearing Aid; Cochlear Implantation. (koene2022hearinglosscleft pages 1-3, andreoletti2017ammecr1asingle pages 6-6)
  • Palate/feeding/speech: cleft-palate repair plus speech-language and feeding therapy. Hearing aids and palate repair were followed by improved speech/language in the original family. NCIT: Cleft Palate Repair/Palatoplasty; Speech Therapy; Supportive Care. (andreoletti2017ammecr1asingle pages 6-6)
  • Development: early intervention, educational support, physical and occupational therapy according to hypotonia and motor delay.
  • Renal: nephrology surveillance and treatment guided by urine chemistry and renal function. Hydration and stone-prevention therapy should be individualized; no AMMECR1-specific alkali or thiazide evidence exists.
  • Growth/skeleton: nutrition and endocrine evaluation, vitamin/mineral assessment where osteopenia is present, orthopedic management, and physiotherapy. Growth hormone produced a response in one patient, but this is anecdotal and not a validated syndrome-specific treatment. (moysesoliveira2018inactivationofammecr1 pages 4-6)
  • Cardiac/ocular/urogenital: standard lesion-specific surveillance and intervention.

No MFHEIN/AMMECR1 interventional NCT study was identified, and treatment-response rates or syndrome-specific adverse-event statistics are unavailable.

13. Prevention

Primary lifestyle prevention is not possible for a germline Mendelian disorder. Primary reproductive options after molecular diagnosis include genetic counseling, familial variant testing, prenatal diagnosis, and preimplantation genetic testing where legally and clinically available.

Secondary prevention consists of early diagnosis through cascade testing and prompt audiology, palate/feeding, developmental, renal, cardiac, and skeletal evaluation. Tertiary prevention aims to reduce communication disability, renal complications, orthopedic morbidity, and developmental disadvantage through surveillance and timely treatment. Vaccination, antimicrobial prophylaxis, public-health sanitation, and environmental remediation have no disease-specific role.

14. Other species and natural disease

No naturally occurring veterinary MFHEIN analogue or zoonotic transmission is established. The relevant orthologues are Ammecr1 in mouse (Mus musculus, NCBITaxon:10090) and ammecr1 in zebrafish (Danio rerio, NCBITaxon:7955). Human and mouse AMMECR1 proteins were reported to share approximately 95.2% amino-acid identity, including putative localization signals, supporting strong evolutionary conservation. No affected animal breed or VBO term is applicable.

15. Model organisms

A zebrafish morpholino model is the principal functional organismal evidence. An exon-3/intron-3 morpholino altered approximately 90% of ammecr1 transcripts: about 65% showed exon-3 skipping with frameshift and 25% carried a 24-bp exon-3 deletion. Knockdown generated developmental phenotypes resembling patient growth, skeletal, and cardiac abnormalities; additional morpholinos and negative controls were used to address nonspecific effects. Morpholino models nevertheless have transient knockdown and off-target limitations and do not establish complete recapitulation of human hearing, erythrocyte, or renal disease. (moysesoliveira2018inactivationofammecr1 pages 6-8, moysesoliveira2018inactivationofammecr1 pages 1-2)

Mouse orthologues have been cloned and mapped, but the retrieved evidence did not establish a disease-specific knockout/knock-in mouse with full MFHEIN phenotyping. No validated patient iPSC, organoid, humanized model, or CRISPR knock-in model was identified.

Evidence assessment and research priorities

The most authoritative interpretation is that AMMECR1 loss or dysfunction causes an X-linked developmental syndrome with growth, craniofacial, auditory, skeletal, cardiac, neurodevelopmental, and erythrocyte manifestations, while nephrocalcinosis and several rarer findings remain incompletely attributable. Experts have appropriately broadened the phenotype beyond the four words in “MFHEIN,” and the female-carrier study demonstrates that “recessive” should not be interpreted as clinically silent in every heterozygous female. (moysesoliveira2018inactivationofammecr1 pages 4-6, koene2022hearinglosscleft pages 4-5)

Highest-priority gaps are: an international patient registry; standardized HPO phenotyping; longitudinal audiology, renal, hematologic, growth, and cardiac data; current ClinVar/gnomAD curation; biochemical identification of the AMMECR1 substrate; stable CRISPR animal/cellular models; and direct comparison of isolated AMMECR1 variants with precisely mapped multigene deletions. Until these data exist, reported manifestations should be annotated with patient-level evidence and uncertainty rather than fixed frequencies.

References

  1. (andreoletti2017ammecr1asingle pages 1-1): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  2. (moysesoliveira2018inactivationofammecr1 pages 2-3): Mariana Moysés-Oliveira, Giuliana Giannuzzi, Richard J. Fish, Jill A. Rosenfeld, Florence Petit, Maria de Fatima Soares, Leslie Domenici Kulikowski, Adriana Di-Battista, Malú Zamariolli, Fan Xia, Thomas Liehr, Nadezda Kosyakova, Gianna Carvalheira, Michael Parker, Eleanor G. Seaby, Sarah Ennis, Rodney D. Gilbert, R. Tanner Hagelstrom, Maria L. Cremona, Wenhui L. Li, Alka Malhotra, Anjana Chandrasekhar, Denise L. Perry, Ryan J. Taft, Julie McCarrier, Donald G. Basel, Joris Andrieux, Taiza Stumpp, Fernanda Antunes, Gustavo José Pereira, Marguerite Neerman-Arbez, Vera Ayres Meloni, Margaret Drummond-Borg, Maria Isabel Melaragno, and Alexandre Reymond. Inactivation of ammecr1 is associated with growth, bone, and heart alterations. Human Mutation, 39:281-291, Feb 2018. URL: https://doi.org/10.1002/humu.23373, doi:10.1002/humu.23373. This article has 20 citations and is from a domain leading peer-reviewed journal.

  3. (andreoletti2017ammecr1asingle pages 5-6): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  4. (poreau2019xq22.3q23microdeletionharboring pages 4-5): Brice Poreau, Francis Ramond, Radu Harbuz, Véronique Satre, Claire Barro, Claire Vettier, Véronique Adouard, Julien Thevenon, Pierre‐Simon Jouk, Charles Coutton, Renaud Touraine, and Klaus Dieterich. Xq22.3q23 microdeletion harboring tmem164 and ammecr1 genes: two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis. American Journal of Medical Genetics Part A, 179:650-654, Apr 2019. URL: https://doi.org/10.1002/ajmg.a.61057, doi:10.1002/ajmg.a.61057. This article has 7 citations.

  5. (moysesoliveira2018inactivationofammecr1 pages 1-2): Mariana Moysés-Oliveira, Giuliana Giannuzzi, Richard J. Fish, Jill A. Rosenfeld, Florence Petit, Maria de Fatima Soares, Leslie Domenici Kulikowski, Adriana Di-Battista, Malú Zamariolli, Fan Xia, Thomas Liehr, Nadezda Kosyakova, Gianna Carvalheira, Michael Parker, Eleanor G. Seaby, Sarah Ennis, Rodney D. Gilbert, R. Tanner Hagelstrom, Maria L. Cremona, Wenhui L. Li, Alka Malhotra, Anjana Chandrasekhar, Denise L. Perry, Ryan J. Taft, Julie McCarrier, Donald G. Basel, Joris Andrieux, Taiza Stumpp, Fernanda Antunes, Gustavo José Pereira, Marguerite Neerman-Arbez, Vera Ayres Meloni, Margaret Drummond-Borg, Maria Isabel Melaragno, and Alexandre Reymond. Inactivation of ammecr1 is associated with growth, bone, and heart alterations. Human Mutation, 39:281-291, Feb 2018. URL: https://doi.org/10.1002/humu.23373, doi:10.1002/humu.23373. This article has 20 citations and is from a domain leading peer-reviewed journal.

  6. (koene2022hearinglosscleft pages 1-3): Saskia Koene, Jeroen Knijnenburg, Mariette J. V. Hoffer, Fleur Zwanenburg, Monique C. Haak, Heiko Locher, Edward S. A. van Beelen, Gijs W. E. Santen, and Liselotte J. C. Rotteveel. Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of ammecr1. American Journal of Medical Genetics. Part a, 188:1578-1582, Jan 2022. URL: https://doi.org/10.1002/ajmg.a.62669, doi:10.1002/ajmg.a.62669. This article has 5 citations and is from a peer-reviewed journal.

  7. (andreoletti2017ammecr1asingle pages 3-4): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  8. (moysesoliveira2018inactivationofammecr1 pages 4-6): Mariana Moysés-Oliveira, Giuliana Giannuzzi, Richard J. Fish, Jill A. Rosenfeld, Florence Petit, Maria de Fatima Soares, Leslie Domenici Kulikowski, Adriana Di-Battista, Malú Zamariolli, Fan Xia, Thomas Liehr, Nadezda Kosyakova, Gianna Carvalheira, Michael Parker, Eleanor G. Seaby, Sarah Ennis, Rodney D. Gilbert, R. Tanner Hagelstrom, Maria L. Cremona, Wenhui L. Li, Alka Malhotra, Anjana Chandrasekhar, Denise L. Perry, Ryan J. Taft, Julie McCarrier, Donald G. Basel, Joris Andrieux, Taiza Stumpp, Fernanda Antunes, Gustavo José Pereira, Marguerite Neerman-Arbez, Vera Ayres Meloni, Margaret Drummond-Borg, Maria Isabel Melaragno, and Alexandre Reymond. Inactivation of ammecr1 is associated with growth, bone, and heart alterations. Human Mutation, 39:281-291, Feb 2018. URL: https://doi.org/10.1002/humu.23373, doi:10.1002/humu.23373. This article has 20 citations and is from a domain leading peer-reviewed journal.

  9. (andreoletti2017ammecr1asingle pages 6-7): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  10. (andreoletti2017ammecr1asingle pages 7-8): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  11. (andreoletti2017ammecr1asingle pages 8-8): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  12. (andreoletti2017ammecr1asingle pages 1-2): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  13. (andreoletti2017ammecr1asingle pages 3-3): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  14. (koene2022hearinglosscleft pages 4-5): Saskia Koene, Jeroen Knijnenburg, Mariette J. V. Hoffer, Fleur Zwanenburg, Monique C. Haak, Heiko Locher, Edward S. A. van Beelen, Gijs W. E. Santen, and Liselotte J. C. Rotteveel. Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of ammecr1. American Journal of Medical Genetics. Part a, 188:1578-1582, Jan 2022. URL: https://doi.org/10.1002/ajmg.a.62669, doi:10.1002/ajmg.a.62669. This article has 5 citations and is from a peer-reviewed journal.

  15. (koene2022hearinglosscleft pages 3-4): Saskia Koene, Jeroen Knijnenburg, Mariette J. V. Hoffer, Fleur Zwanenburg, Monique C. Haak, Heiko Locher, Edward S. A. van Beelen, Gijs W. E. Santen, and Liselotte J. C. Rotteveel. Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of ammecr1. American Journal of Medical Genetics. Part a, 188:1578-1582, Jan 2022. URL: https://doi.org/10.1002/ajmg.a.62669, doi:10.1002/ajmg.a.62669. This article has 5 citations and is from a peer-reviewed journal.

  16. (andreoletti2017ammecr1asingle pages 4-5): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  17. (andreoletti2017ammecr1asingle pages 6-6): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  18. (andreoletti2017ammecr1asingle pages 8-9): Gaia Andreoletti, Eleanor G Seaby, Jennifer M Dewing, Ita O'Kelly, Katherine Lachlan, Rodney D Gilbert, and Sarah Ennis. Ammecr1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. Journal of Medical Genetics, 54:269-277, Nov 2017. URL: https://doi.org/10.1136/jmedgenet-2016-104100, doi:10.1136/jmedgenet-2016-104100. This article has 19 citations and is from a domain leading peer-reviewed journal.

  19. (moysesoliveira2018inactivationofammecr1 pages 6-8): Mariana Moysés-Oliveira, Giuliana Giannuzzi, Richard J. Fish, Jill A. Rosenfeld, Florence Petit, Maria de Fatima Soares, Leslie Domenici Kulikowski, Adriana Di-Battista, Malú Zamariolli, Fan Xia, Thomas Liehr, Nadezda Kosyakova, Gianna Carvalheira, Michael Parker, Eleanor G. Seaby, Sarah Ennis, Rodney D. Gilbert, R. Tanner Hagelstrom, Maria L. Cremona, Wenhui L. Li, Alka Malhotra, Anjana Chandrasekhar, Denise L. Perry, Ryan J. Taft, Julie McCarrier, Donald G. Basel, Joris Andrieux, Taiza Stumpp, Fernanda Antunes, Gustavo José Pereira, Marguerite Neerman-Arbez, Vera Ayres Meloni, Margaret Drummond-Borg, Maria Isabel Melaragno, and Alexandre Reymond. Inactivation of ammecr1 is associated with growth, bone, and heart alterations. Human Mutation, 39:281-291, Feb 2018. URL: https://doi.org/10.1002/humu.23373, doi:10.1002/humu.23373. This article has 20 citations and is from a domain leading peer-reviewed journal.

  20. (poreau2019xq22.3q23microdeletionharboring pages 4-4): Brice Poreau, Francis Ramond, Radu Harbuz, Véronique Satre, Claire Barro, Claire Vettier, Véronique Adouard, Julien Thevenon, Pierre‐Simon Jouk, Charles Coutton, Renaud Touraine, and Klaus Dieterich. Xq22.3q23 microdeletion harboring tmem164 and ammecr1 genes: two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis. American Journal of Medical Genetics Part A, 179:650-654, Apr 2019. URL: https://doi.org/10.1002/ajmg.a.61057, doi:10.1002/ajmg.a.61057. This article has 7 citations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 4
On topic 3
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 30
Resolved 29
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 0
Terms whose name was checked 2
Terms named correctly 0
Terms named as a different term 0
Terms whose name is worth a second look 2

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0010985 (obsolete Gonosomal inheritance) (1 mention) - replaced by HP:0000005

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0010985 (1 mention) - the report calls it "X-linked inheritance"; HP calls it obsolete Gonosomal inheritance
  • GO:0005634 (3 mentions) - the report calls it "GO: nucleus"; GO calls it nucleus

29 of 30 terms resolved to a current term; the rest could not be looked up either way.