Intellectual Developmental Disorder With Autism And Dysmorphic Facies

Mendelian MONDO:0859281 Pathograph 17 Show in embeddings browser Neurodevelopmental disorder Syndromic intellectual disability

An autosomal recessive syndromic intellectual disability caused by homozygous premature termination codons in PDZD8, an endoplasmic reticulum (ER) transmembrane lipid transfer protein that tethers the ER to late endosomes/lysosomes and to mitochondria. Six affected individuals from three consanguineous families (Omani, Emirati and Afghan) have been reported, homozygous for p.(Q30*), p.(Y298*) or p.(S733*). All six have developmental delay, intellectual disability (severe in four), autistic behaviour (autism spectrum disorder diagnosed in five) and facial dysmorphism, with orbital hypertelorism, malar flattening, a myopathic or hypotonic face and an open mouth. Mild muscle weakness, epilepsy, myopia, marfanoid habitus or short stature, scoliosis and ADHD occur in some. Pdzd8 mutant mice show reduced preweaning viability, repetitive jumping, social recognition deficits, impaired long-term spatial memory and reduced hippocampal long-term potentiation, and fly knockdown impairs long-term memory. Cellular studies place PDZD8 at ER-endolysosome contacts, where its lipid transfer promotes endosome maturation, lipophagy and neurite outgrowth, and at ER-mitochondria contacts, where it couples synaptic ER calcium release to mitochondrial uptake. Management is supportive.

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Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
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Inheritance

1
Autosomal recessive inheritance HP:0000007
All six affected individuals are homozygous for a PDZD8 premature termination codon and are children of first-cousin marriages. Heterozygous relatives do not have syndromic intellectual disability. In family A the carrier parents had mild myopathy and reduced facial expression and the father had mild autistic features; the authors nonetheless judge PDZD8 haploinsufficiency unlikely to have a major effect.
Autosomal recessive inheritance
Show evidence (4 references)
PMID:35227461 SUPPORT Human clinical
"Homozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum-anchored lipid transfer protein, showed cosegregation with syndromic ID in both families."
Homozygous variants cosegregating with disease in two consanguineous families.
PMID:35227461 SUPPORT Human clinical
"our finding that syndromic ID is absent from heterozygotes in families A and B suggests that PDZD8 haploinsufficiency is unlikely to have a major impact"
Heterozygotes do not have the syndrome.
PMID:40016860 SUPPORT Human clinical
"The pedigree structure of family C suggested autosomal recessive transmission of a homozygous mutant allele from a shared ancestor as the most likely explanation for the condition of the two affected siblings."
The third family also fits autosomal recessive transmission.
+ 1 more reference
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Discussions and Knowledge Gaps

1
Which PDZD8 function explains the muscle weakness, facial dysmorphism and short stature of IDDADF, and which of the two contact-site roles (ER-endolysosome lipid transfer or ER-mitochondria calcium coupling) drives the neurodevelopmental phenotype?
KNOWLEDGE GAP OPEN iddadf_nonneural_features
Attached to
phenotypes#Muscle Weakness phenotypes#Facial Dysmorphism phenotypes#Short Stature pathophysiology#Impaired ER-Mitochondria Calcium Coupling pathophysiology#Impaired Endolysosome Maturation
The mechanistic evidence comes from cultured cells, flies and mice; no patient cells have been studied, and PDZD8 protein is not detectable in blood. The mouse studies link the cognitive phenotype to synaptic plasticity and brain lipid accumulation but do not separate the endolysosomal and mitochondrial roles. No source cited here addresses the muscle, craniofacial or growth features, and in family A a second homozygous ANKRD2 variant may contribute to the myopathy.
Show evidence (1 reference)
PMID:35227461 SUPPORT Human clinical
"The lack of PDZD8 protein in human blood limits our ability to detect truncated PDZD8 proteins (31)."
Patient protein studies have not been possible from blood.
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Pathophysiology

6
PDZD8 Biallelic Loss of Function
Both PDZD8 alleles carry a premature termination codon (p.Q30* in exon 1, p.Y298* in exon 2, p.S733* in the last exon). Any protein escaping nonsense-mediated decay would keep the ER transmembrane anchor but lack the C-terminal regions that bind protrudin, late-endosome/lysosome phospholipids and Rab7, so no functional full-length protein is expected. PDZD8's SMP domain binds and transfers glycerophospholipids and ceramides between membranes, and the protein tethers the ER to late endosomes/lysosomes and to mitochondria. These activities are the gene's established functions; they were not measured on the patient alleles.
PDZD8 hgnc:26974 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PDZD8 (hgnc:26974). hgnc:26974 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
lipid transfer activity GO:0120013 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased lipid transfer activity (GO:0120013). GO:0120013 is a molecular function from the Gene Ontology. endoplasmic reticulum-endosome tether activity GO:0170016 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased endoplasmic reticulum-endosome tether activity (GO:0170016). GO:0170016 is a molecular function from the Gene Ontology. mitochondrion-endoplasmic reticulum membrane tether activity GO:0140474 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased mitochondrion-endoplasmic reticulum membrane tether activity (GO:0140474). GO:0140474 is a molecular function from the Gene Ontology.
Downstream
Impaired Endolysosome Maturation
Impaired ER-Mitochondria Calcium Coupling
Show evidence (5 references)
PMID:35227461 SUPPORT Human clinical
"These data demonstrate the involvement of homozygous loss-of-function mutations in PDZD8 in a neurodevelopmental cognitive disorder."
The defining study interprets the homozygous truncating variants as loss of function.
PMID:35227461 SUPPORT INDIRECT Human clinical
"If a PTC-bearing allele does escape detection by NMD, protein translation would stop prematurely, and thus no functional full-length PDZD8 protein would be produced."
Argument that even the last-exon allele yields no functional full-length protein; not measured directly.
PMID:33912962 SUPPORT In vitro / ex vivo
"Furthermore, we discover that the SMP domain of PDZD8 binds glycerophospholipids and ceramides both in vivo and in vitro, and that the SMP domain can transport lipids between membranes in vitro."
Direct biochemical evidence for PDZD8 lipid transfer activity.
+ 2 more references
Impaired Endolysosome Maturation
Without PDZD8-mediated lipid supply at ER-late endosome/lysosome contacts, endosome maturation fails. PDZD8- or protrudin-depleted mouse neurons form abnormal large vacuoles, and in Drosophila PDZD8 is needed for lysosome maturation and autophagic flux at these contacts.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
endosome organization GO:0007032 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal endosome organization (GO:0007032). GO:0007032 is a biological process from the Gene Ontology. lysosome organization GO:0007040 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal lysosome organization (GO:0007040). GO:0007040 is a biological process from the Gene Ontology.
Downstream
Impaired Neurite Outgrowth and Synapse Development
Brain Cholesteryl Ester Accumulation
Show evidence (2 references)
PMID:32917905 SUPPORT In vitro / ex vivo
"Our results suggest that protrudin and PDZD8 cooperatively promote endosome maturation by mediating ER-LyLE tethering and lipid extraction at MCSs, thereby maintaining neuronal polarity and integrity."
Endosome maturation depends on PDZD8 tethering and lipid extraction.
PMID:40156832 SUPPORT Model organism
"PDZD8 accelerates autophagic flux by promoting lysosome maturation at ER-late endosome/lysosome MCSs."
In Drosophila neurons PDZD8 promotes lysosome maturation and autophagy.
Brain Cholesteryl Ester Accumulation
PDZD8-knockout mice accumulate cholesteryl esters in the brain because lipid droplets are not cleared by lipophagy; cholesterol synthesis is normal and diet does not change the accumulation. This is shown only in mice; brain lipids have not been measured in patients.
lipophagy GO:0061724 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased lipophagy (GO:0061724). GO:0061724 is a biological process from the Gene Ontology.
Downstream
Intellectual Disability
Show evidence (1 reference)
PMID:36465123 SUPPORT Model organism
"Here we show that CEs accumulate in the brain of PDZD8-deficient mice as a result of impaired lipophagy."
Brain cholesteryl ester accumulation in PDZD8 knockout mice.
Impaired ER-Mitochondria Calcium Coupling
PDZD8 is needed for ER-mitochondria contacts. In cortical neurons its loss stops mitochondria taking up calcium released from the ER after synaptic stimulation, so cytosolic calcium rises higher in dendrites.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
mitochondrial calcium ion homeostasis GO:0051560 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mitochondrial calcium ion homeostasis (GO:0051560). GO:0051560 is a biological process from the Gene Ontology.
Downstream
Hippocampal Synaptic Plasticity Deficit
Show evidence (1 reference)
PMID:29097544 SUPPORT In vitro / ex vivo
"In neurons, PDZD8 was required for calcium ion (Ca2+) uptake by mitochondria after synaptically induced Ca2+-release from ER and thereby regulated cytoplasmic Ca2+ dynamics."
PDZD8 couples ER calcium release to mitochondrial uptake in neurons.
Impaired Neurite Outgrowth and Synapse Development
PDZD8 depletion reduces neurite outgrowth in cultured cells, disrupts neuronal polarity, and in Drosophila blocks activity-dependent synaptic bouton formation. Pdzd8 mutant mice have increased dendritic spine density and reduced adult neurogenesis.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
neuron projection development GO:0031175 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron projection development (GO:0031175). GO:0031175 is a biological process from the Gene Ontology. synapse organization GO:0050808 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal synapse organization (GO:0050808). GO:0050808 is a biological process from the Gene Ontology.
Animal models
Pdzd8tm1b mouse Mouse partially recapitulates Increased dendritic spine density and reduced adult neurogenesis in mutant brain.
Downstream
Hippocampal Synaptic Plasticity Deficit
Show evidence (3 references)
PMID:33912962 SUPPORT In vitro / ex vivo
"Functionally, PDZD8 is required for LE/lys positioning and neurite outgrowth, which is dependent on the lipid transfer activity of the SMP domain."
PDZD8 is required for neurite outgrowth.
PMID:40156832 SUPPORT Model organism
"We find that PDZD8 is required for activity-dependent synaptic bouton formation in multiple paradigms."
Synaptic bouton formation in Drosophila requires PDZD8.
PMID:40016860 SUPPORT Model organism
"In the brain, Pdzd8tm1b mice exhibit increased levels of accessory olfactory bulb volume, primary olfactory cortex volume, dendritic spine density, and ER stress- and mitochondrial fusion-related transcripts, as well as decreased levels of cerebellar nuclei volume and adult neurogenesis."
Mutant mice have altered dendritic spine density and brain region volumes.
Hippocampal Synaptic Plasticity Deficit
Pdzd8 mutant mice have reduced hippocampal long-term potentiation under maximal (3x theta burst) stimulation but not under submaximal protocols, together with impaired long-term spatial memory; fly knockdown impairs long-term courtship memory. Only the LTP reduction is bound as a process here; the memory deficits are organism-level behaviour and are carried by the intellectual disability phenotype. The authors read the cognitive impairment as a synaptopathy.
long-term synaptic potentiation GO:0060291 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased long-term synaptic potentiation (GO:0060291). GO:0060291 is a biological process from the Gene Ontology.
Animal models
Pdzd8tm1b mouse Mouse recapitulates Reduced hippocampal LTP and impaired long-term spatial memory.
Drosophila PDZD8 knockdown Fruit fly partially recapitulates Long-term memory deficit.
Downstream
Intellectual Disability
Global Developmental Delay
Autistic Behavior
Show evidence (2 references)
PMID:35227461 SUPPORT Model organism
"Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits."
Synaptic plasticity and spatial memory deficits in mutant mice.
PMID:35227461 SUPPORT Model organism
"Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory."
Long-term memory deficit in flies.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Intellectual Developmental Disorder With Autism And Dysmorphic Facies 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

25
Eye 3
Hypertelorism FREQUENT HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Orbital Hypertelorism | No | No | 4/6"
Present in 4 of 6 cases.
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35227461 SUPPORT Human clinical
"dysmorphic features (low-set ears with simple helix, bilateral ptosis)"
Bilateral ptosis in family B.
Myopia FREQUENT HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Myopia | No | No | 2/6"
Present in 2 of 6 cases.
Head and Neck 7
Facial Dysmorphism OBLIGATE Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Facial Dysmorphism | Yes | Yes | 6/6"
Present in 6 of 6 cases.
Malar Flattening HP:0000272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malar flattening (HP:0000272). HP:0000272 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35227461 SUPPORT Human clinical
"facial dysmorphism (myopathic face with orbital hypertelorism, malar flattening, open mouth, and high-arched palate)"
Malar flattening in family A.
PMID:40016860 SUPPORT Human clinical
"They present facial dysmorphism (hypotonic face, malar flattening, thin palpebral fissures, and open mouth)"
Malar flattening in family C.
Myopathic Facies HP:0002058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathic facies (HP:0002058). HP:0002058 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35227461 SUPPORT Human clinical
"facial dysmorphism (myopathic face with orbital hypertelorism, malar flattening, open mouth, and high-arched palate)"
Myopathic face in family A.
Facial Hypotonia HP:0000297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial hypotonia (HP:0000297). HP:0000297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"They present facial dysmorphism (hypotonic face, malar flattening, thin palpebral fissures, and open mouth)"
Hypotonic face in family C.
Open Mouth HP:0000194 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Open mouth (HP:0000194). HP:0000194 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35227461 SUPPORT Human clinical
"facial dysmorphism (myopathic face with orbital hypertelorism, malar flattening, open mouth, and high-arched palate)"
Open mouth in family A.
PMID:40016860 SUPPORT Human clinical
"They present facial dysmorphism (hypotonic face, malar flattening, thin palpebral fissures, and open mouth)"
Open mouth in family C.
High Palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35227461 SUPPORT Human clinical
"facial dysmorphism (myopathic face with orbital hypertelorism, malar flattening, open mouth, and high-arched palate)"
High-arched palate in family A.
Narrow Palpebral Fissure HP:0045025 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow palpebral fissure (HP:0045025). HP:0045025 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"They present facial dysmorphism (hypotonic face, malar flattening, thin palpebral fissures, and open mouth)"
Thin palpebral fissures in family C.
Musculoskeletal 2
Muscle Weakness VERY_FREQUENT HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40016860 SUPPORT Human clinical
"Myasthenia | Yes (mild) | Yes (mild) | 5/6 (mild: 3/6)"
Present in 5 of 6 cases.
PMID:35227461 SUPPORT Human clinical
"However, because ANKRD2 is upregulated in congenital myopathies (33), p.(R328W) homozygosity may contribute to myopathy in family A."
A second homozygous variant may contribute to the muscle phenotype in family A.
Scoliosis FREQUENT HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Scoliosis | Yes | No | 2/6"
Present in 2 of 6 cases.
Nervous System 11
Global Developmental Delay OBLIGATE 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.
Show evidence (2 references)
PMID:40016860 SUPPORT Human clinical
"The discovery of a third family with IDDADF caused by biallelic disruption of PDZD8 permitted identification of a core clinical phenotype consisting of developmental delay, ID, autism, and facial dysmorphism."
Developmental delay is part of the core phenotype.
PMID:40016860 SUPPORT Human clinical
"Developmental Delay | Yes | Yes | 6/6"
Present in 6 of 6 cases.
Intellectual Disability OBLIGATE HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40016860 SUPPORT Human clinical
"Intellectual Disability | Yes (severe) | Yes (severe) | 6/6 (severe: 4/6)"
Present in 6 of 6, severe in 4.
PMID:35227461 SUPPORT Human clinical
"Clinical examination revealed that all affected individuals have moderate to severe ID with autistic features, myopathy, and facial dysmorphism"
Moderate to severe ID in family A.
Autistic Behavior OBLIGATE HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Our finding that the Pdzd8tm1b mouse model and all six known cases of IDDADF exhibit autistic behavior, with ASD diagnosed in five cases, identifies this trait as a common outcome of biallelic disruption of PDZD8 in humans and mice."
Autistic behaviour in all six cases, ASD in five.
Motor Stereotypy HP:0000733 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor stereotypy (HP:0000733). HP:0000733 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35227461 SUPPORT Human clinical
"mild autistic features (echolalia, jumping, hand flapping, lack of eye contact)"
Hand flapping and jumping in the family B proband.
Echolalia HP:0010529 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Echolalia (HP:0010529). HP:0010529 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35227461 SUPPORT Human clinical
"mild autistic features (echolalia, jumping, hand flapping, lack of eye contact)"
Echolalia in the family B proband.
Attention Deficit Hyperactivity Disorder FREQUENT HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"ADHD | No | No | 2/6"
Present in 2 of 6 cases.
Absent Speech HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Neuropsychological assessments revealed that both the index case (C.IV.1) and his affected sister (C.IV.2) have severe ASD, severe ID, and a lack of functional language"
No functional language in both family C siblings.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Epilepsy | Yes | No | 3/6"
Present in 3 of 6 cases.
Cerebral White Matter Abnormality Abnormal cerebral white matter morphology HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Brain MRI revealed cortico-subcortical frontal and parietal demyelinating lesions with mild cerebellar hemispheric atrophy in C.IV.1 (Fig. 1F, G) and subcortical aspecific gliotic lesions in C.IV.2."
White matter lesions in both family C siblings.
Cerebellar Atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Brain MRI revealed cortico-subcortical frontal and parietal demyelinating lesions with mild cerebellar hemispheric atrophy in C.IV.1 (Fig. 1F, G) and subcortical aspecific gliotic lesions in C.IV.2."
Mild cerebellar atrophy in C.IV.1.
Hypoplasia of the Corpus Callosum HP:0002079 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the corpus callosum (HP:0002079). HP:0002079 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35227461 SUPPORT Human clinical
"Brain Scan Findings | ND | ND | Hypoplasia of splenium of corpus callosum | Normal"
Splenial hypoplasia in A.IV.5.
Growth 2
Marfanoid Habitus FREQUENT Disproportionate tall stature HP:0001519 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Marfanoid habitus, annotated with Disproportionate tall stature (HP:0001519). HP:0001519 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Marfanoid Habitus | No | No | 2/6"
Present in 2 of 6 cases.
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.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"a proportional short stature, with a height more than three standard deviations below the mean for age and sex"
Short stature in both family C siblings.
🧬

Genetic Associations

1
PDZD8
Gene: PDZD8 hgnc:26974 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PDZD8 (hgnc:26974). hgnc:26974 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:35227461 SUPPORT Human clinical
"Homozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum-anchored lipid transfer protein, showed cosegregation with syndromic ID in both families."
First report linking PDZD8 to the disorder.
PMID:40016860 SUPPORT Human clinical
"Intellectual developmental disorder with autism and dysmorphic facies (IDDADF) is a rare syndromic intellectual disability (ID) caused by homozygous disruption of PDZD8 (PDZ domain-containing protein 8), an integral endoplasmic reticulum (ER) protein."
Confirmation in a third family.
Variants (3)
NM_173791.5:c.88C>T (p.Gln30Ter)
single nucleotide variant
Variant detail: nonsense
Homozygous in family C (Afghan origin, two affected siblings). Exon 1. One heterozygote in gnomAD v4.1.0.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"identified a homozygous nonsense variant in PDZD8 exon 1"
Identity of the family C variant.
NM_173791.5:c.894C>G (p.Tyr298Ter)
single nucleotide variant
Variant detail: nonsense
Homozygous in family B (Emirati, one affected boy). Exon 2. Absent from gnomAD.
Show evidence (1 reference)
PMID:35227461 SUPPORT Human clinical
"revealed a homozygous nonsense variant in PDZD8 exon 2"
Identity of the family B variant.
NM_173791.5:c.2197_2200del (p.Ser733Ter)
deletion
Variant detail: frameshift
Homozygous in family A (Omani, three affected siblings). A 4-bp deletion in the last exon introducing a frameshift and premature termination codon. Absent from gnomAD.
Show evidence (1 reference)
PMID:35227461 SUPPORT Human clinical
"The PDZD8 c.2197_2200del variant deletes four base pairs in exon 5, introducing a frameshift and PTC (Figure 1C and Table 2) absent from gnomAD."
Identity of the family A variant.
💊

Medical Actions

2
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: valproic acid CHEBI:39867 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses valproic acid (CHEBI:39867). CHEBI:39867 is a therapeutic agent from Chemical Entities of Biological Interest. levetiracetam CHEBI:6437 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levetiracetam (CHEBI:6437). CHEBI:6437 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The family C index case with generalized epilepsy was treated with valproic acid and levetiracetam. No disease-specific treatment exists.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"In addition, C.IV.1 presents scoliosis and generalized epilepsy treated by valproic acid (VPA) and levetiracetam"
Single-patient report of the treatment used; response is not described.
Genetic Counseling
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counseling and carrier screening for consanguineous families, as proposed by the defining study.
Show evidence (1 reference)
PMID:35227461 SUPPORT Human clinical
"This knowledge will benefit affected families through genetic counseling and carrier screening and facilitate the genetic diagnosis of other patients."
The authors recommend genetic counseling and carrier screening.
🔬

Diagnosis

1
Exome Sequencing
All three families were diagnosed by homozygosity mapping and whole-exome sequencing with segregation analysis. The core phenotype of developmental delay, intellectual disability, autism and facial dysmorphism is the clinical clue.
exome sequencing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40016860 SUPPORT Human clinical
"Homozygosity mapping, whole-exome sequencing, and cosegregation analysis were used to identify the PDZD8 variant responsible for IDDADF, including diagnoses of ASD, in consanguineous family C."
Diagnostic route used in family C.
📊

Prevalence

1
Worldwide
Cases/families reported in the literature Ultra-rare
Six individuals from three consanguineous families (Omani, Emirati and Afghan) are published. No population rate is available.
Show evidence (2 references)
PMID:40016860 SUPPORT Human clinical
"The total number of known cases of PDZD8-related IDDADF remains low."
The authors state the case count is low.
PMID:40016860 SUPPORT Human clinical
"The identification of six IDDADF cases (4 male and 2 female), with three different PDZD8 PTC variants and ethnic origins"
Six published cases in total.
🐁

Animal Models

2
Pdzd8tm1b mouse
Homozygous mice have reduced preweaning viability, smaller body and brain size, spontaneous repetitive hindlimb jumping, impaired long-term spatial memory, reduced long-term potentiation after maximal stimulation, impaired social recognition and social odour discrimination, dark-phase hyperactivity and increased metabolic rate.
Species
Mouse
Genotype
Pdzd8tm1b homozygous (exon 3 replaced by lacZ cassette; p.F333Nfs1*), C57BL/6NTac
Publication
PMID:35227461
Pathograph links
Hippocampal Synaptic Plasticity Deficit recapitulates fidelity: moderate observes: tissue Reduced hippocampal LTP and impaired long-term spatial memory.
Limitations: The LTP deficit appears only with maximal 3x theta burst stimulation and not with submaximal protocols; spatial learning itself is intact.
Show evidence (1 reference)
PMID:35227461 SUPPORT Model organism
"Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits."
The model shows the plasticity and memory deficits.
Impaired Neurite Outgrowth and Synapse Development partially recapitulates fidelity: unknown observes: tissue Increased dendritic spine density and reduced adult neurogenesis in mutant brain.
Limitations: Spine density is increased rather than reduced, so the direction of the synaptic change differs from the reduced neurite outgrowth seen in cultured cells; neurite outgrowth itself was not measured in the mouse.
Show evidence (1 reference)
PMID:40016860 SUPPORT Model organism
"In the brain, Pdzd8tm1b mice exhibit increased levels of accessory olfactory bulb volume, primary olfactory cortex volume, dendritic spine density, and ER stress- and mitochondrial fusion-related transcripts, as well as decreased levels of cerebellar nuclei volume and adult neurogenesis."
Spine density and neurogenesis changes in the mutant mouse brain.
Drosophila PDZD8 knockdown
Knockdown flies have impaired long-term courtship-based memory.
Species
Fruit fly
Genotype
RNAi knockdown of the PDZD8 ortholog
Publication
PMID:35227461
Pathograph links
Hippocampal Synaptic Plasticity Deficit partially recapitulates fidelity: low observes: organism Long-term memory deficit.
Limitations: Invertebrate behavioural memory assay; no hippocampus and no synaptic plasticity measurement.
Show evidence (1 reference)
PMID:35227461 SUPPORT Model organism
"Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory."
Long-term memory deficit in knockdown flies.
{ }

Source YAML

click to show 
name: Intellectual Developmental Disorder With Autism And Dysmorphic Facies
creation_date: "2026-10-23T02:07:54Z"
category: Mendelian
parents:
- Neurodevelopmental disorder
- Syndromic intellectual disability
synonyms:
- IDDADF
- PDZD8-related intellectual developmental disorder
description: >-
  An autosomal recessive syndromic intellectual disability caused by
  homozygous premature termination codons in PDZD8, an endoplasmic reticulum
  (ER) transmembrane lipid transfer protein that tethers the ER to late
  endosomes/lysosomes and to mitochondria. Six affected individuals from three
  consanguineous families (Omani, Emirati and Afghan) have been reported,
  homozygous for p.(Q30*), p.(Y298*) or p.(S733*). All six have developmental
  delay, intellectual disability (severe in four), autistic behaviour (autism
  spectrum disorder diagnosed in five) and facial dysmorphism, with orbital
  hypertelorism, malar flattening, a myopathic or hypotonic face and an open
  mouth. Mild muscle weakness, epilepsy, myopia, marfanoid habitus or short
  stature, scoliosis and ADHD occur in some. Pdzd8 mutant mice show reduced
  preweaning viability, repetitive jumping, social recognition deficits,
  impaired long-term spatial memory and reduced hippocampal long-term
  potentiation, and fly knockdown impairs long-term memory. Cellular studies
  place PDZD8 at ER-endolysosome contacts, where its lipid transfer promotes
  endosome maturation, lipophagy and neurite outgrowth, and at ER-mitochondria
  contacts, where it couples synaptic ER calcium release to mitochondrial
  uptake. Management is supportive.
references:
- reference: PMID:35227461
  title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
- reference: PMID:40016860
  title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
- reference: PMID:29097544
  title: "ER-mitochondria tethering by PDZD8 regulates Ca(2+) dynamics in mammalian neurons."
- reference: PMID:31636202
  title: "PDZD8 mediates a Rab7-dependent interaction of the ER with late endosomes and lysosomes."
- reference: PMID:32917905
  title: "Protrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation."
- reference: PMID:33912962
  title: "PDZD8-mediated lipid transfer at contacts between the ER and late endosomes/lysosomes is required for neurite outgrowth."
- reference: PMID:40156832
  title: "PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth."
- reference: PMID:36465123
  title: "PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy."
- reference: PMID:36658656
  title: "PDZD8-deficient mice manifest behavioral abnormalities related to emotion, cognition, and adaptation due to dyslipidemia in the brain."
disease_term:
  preferred_term: intellectual developmental disorder with autism and dysmorphic facies
  term:
    id: MONDO:0859281
    label: intellectual developmental disorder with autism and dysmorphic facies
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Six individuals from three consanguineous families (Omani, Emirati and
    Afghan) are published. No population rate is available.
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The total number of known cases of PDZD8-related IDDADF remains low."
    explanation: The authors state the case count is low.
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of six IDDADF cases (4 male and 2 female), with three different PDZD8 PTC variants and ethnic origins"
    explanation: Six published cases in total.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All six affected individuals are homozygous for a PDZD8 premature
    termination codon and are children of first-cousin marriages.
    Heterozygous relatives do not have syndromic intellectual disability.
    In family A the carrier parents had mild myopathy and reduced facial
    expression and the father had mild autistic features; the authors
    nonetheless judge PDZD8 haploinsufficiency unlikely to have a major
    effect.
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum-anchored lipid transfer protein, showed cosegregation with syndromic ID in both families."
    explanation: Homozygous variants cosegregating with disease in two consanguineous families.
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our finding that syndromic ID is absent from heterozygotes in families A and B suggests that PDZD8 haploinsufficiency is unlikely to have a major impact"
    explanation: Heterozygotes do not have the syndrome.
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pedigree structure of family C suggested autosomal recessive transmission of a homozygous mutant allele from a shared ancestor as the most likely explanation for the condition of the two affected siblings."
    explanation: The third family also fits autosomal recessive transmission.
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All heterozygous children and parents are asymptomatic."
    explanation: Heterozygous carriers in family C are unaffected.
pathophysiology:
- name: PDZD8 Biallelic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Both PDZD8 alleles carry a premature termination codon (p.Q30* in exon 1,
    p.Y298* in exon 2, p.S733* in the last exon). Any protein escaping
    nonsense-mediated decay would keep the ER transmembrane anchor but lack
    the C-terminal regions that bind protrudin, late-endosome/lysosome
    phospholipids and Rab7, so no functional full-length protein is expected.
    PDZD8's SMP domain binds and transfers glycerophospholipids and ceramides
    between membranes, and the protein tethers the ER to late
    endosomes/lysosomes and to mitochondria. These activities are the gene's
    established functions; they were not measured on the patient alleles.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HOMOZYGOUS
  genes:
  - preferred_term: PDZD8
    term:
      id: hgnc:26974
      label: PDZD8
  molecular_functions:
  - preferred_term: lipid transfer activity
    modifier: DECREASED
    term:
      id: GO:0120013
      label: lipid transfer activity
  - preferred_term: endoplasmic reticulum-endosome tether activity
    modifier: DECREASED
    term:
      id: GO:0170016
      label: endoplasmic reticulum-endosome tether activity
  - preferred_term: mitochondrion-endoplasmic reticulum membrane tether activity
    modifier: DECREASED
    term:
      id: GO:0140474
      label: mitochondrion-endoplasmic reticulum membrane tether activity
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data demonstrate the involvement of homozygous loss-of-function mutations in PDZD8 in a neurodevelopmental cognitive disorder."
    explanation: The defining study interprets the homozygous truncating variants as loss of function.
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "If a PTC-bearing allele does escape detection by NMD, protein translation would stop prematurely, and thus no functional full-length PDZD8 protein would be produced."
    explanation: Argument that even the last-exon allele yields no functional full-length protein; not measured directly.
  - reference: PMID:33912962
    reference_title: "PDZD8-mediated lipid transfer at contacts between the ER and late endosomes/lysosomes is required for neurite outgrowth."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, we discover that the SMP domain of PDZD8 binds glycerophospholipids and ceramides both in vivo and in vitro, and that the SMP domain can transport lipids between membranes in vitro."
    explanation: Direct biochemical evidence for PDZD8 lipid transfer activity.
  - reference: PMID:31636202
    reference_title: "PDZD8 mediates a Rab7-dependent interaction of the ER with late endosomes and lysosomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that PDZD8, an intrinsic membrane protein of the ER with a lipid transport module of the SMP domain family, concentrates at contacts between the ER and late endosomes/lysosomes, where it interacts with GTP-Rab7."
    explanation: PDZD8 tethers the ER to late endosomes/lysosomes through Rab7.
  - reference: PMID:29097544
    reference_title: "ER-mitochondria tethering by PDZD8 regulates Ca(2+) dynamics in mammalian neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PDZD8 was necessary for the formation of ER-mitochondria contacts in mammalian cells."
    explanation: PDZD8 is required for ER-mitochondria tethering.
  downstream:
  - target: Impaired Endolysosome Maturation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32917905
      reference_title: "Protrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Overexpression of both protrudin and PDZD8 in HeLa cells, as well as their depletion in mouse primary neurons, impairs endosomal homeostasis by inducing the formation of abnormal large vacuoles reminiscent of those apparent in spastin- or REEP1-deficient neurons."
      explanation: Depleting PDZD8 in primary neurons disrupts endosomal homeostasis.
  - target: Impaired ER-Mitochondria Calcium Coupling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29097544
      reference_title: "ER-mitochondria tethering by PDZD8 regulates Ca(2+) dynamics in mammalian neurons."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In neurons, PDZD8 was required for calcium ion (Ca2+) uptake by mitochondria after synaptically induced Ca2+-release from ER and thereby regulated cytoplasmic Ca2+ dynamics."
      explanation: Loss of PDZD8 abolishes mitochondrial calcium uptake after synaptic ER calcium release.
- name: Impaired Endolysosome Maturation
  biological_scale: CELLULAR
  description: >-
    Without PDZD8-mediated lipid supply at ER-late endosome/lysosome contacts,
    endosome maturation fails. PDZD8- or protrudin-depleted mouse neurons form
    abnormal large vacuoles, and in Drosophila PDZD8 is needed for lysosome
    maturation and autophagic flux at these contacts.
  biological_processes:
  - preferred_term: endosome organization
    modifier: ABNORMAL
    term:
      id: GO:0007032
      label: endosome organization
  - preferred_term: lysosome organization
    modifier: ABNORMAL
    term:
      id: GO:0007040
      label: lysosome organization
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:32917905
    reference_title: "Protrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our results suggest that protrudin and PDZD8 cooperatively promote endosome maturation by mediating ER-LyLE tethering and lipid extraction at MCSs, thereby maintaining neuronal polarity and integrity."
    explanation: Endosome maturation depends on PDZD8 tethering and lipid extraction.
  - reference: PMID:40156832
    reference_title: "PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "PDZD8 accelerates autophagic flux by promoting lysosome maturation at ER-late endosome/lysosome MCSs."
    explanation: In Drosophila neurons PDZD8 promotes lysosome maturation and autophagy.
  downstream:
  - target: Impaired Neurite Outgrowth and Synapse Development
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33912962
      reference_title: "PDZD8-mediated lipid transfer at contacts between the ER and late endosomes/lysosomes is required for neurite outgrowth."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functionally, PDZD8 is required for LE/lys positioning and neurite outgrowth, which is dependent on the lipid transfer activity of the SMP domain."
      explanation: Neurite outgrowth needs PDZD8 lipid transfer at endolysosome contacts.
    - reference: PMID:40156832
      reference_title: "PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "PDZD8 is sufficient to drive excess synaptic bouton formation through an autophagy-dependent mechanism and required for synapse development when autophagy is limited."
      explanation: In Drosophila, PDZD8-driven autophagy supports synapse development.
  - target: Brain Cholesteryl Ester Accumulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36465123
      reference_title: "PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "PDZD8 may mediate the exchange of cholesterol and phosphatidylserine between ER and Rab7-positive organelles to promote the fusion of CE-containing LDs with lysosomes for their degradation."
      explanation: Lipid droplet-lysosome fusion for lipophagy depends on PDZD8 at Rab7-positive organelles.
- name: Brain Cholesteryl Ester Accumulation
  biological_scale: TISSUE
  description: >-
    PDZD8-knockout mice accumulate cholesteryl esters in the brain because
    lipid droplets are not cleared by lipophagy; cholesterol synthesis is
    normal and diet does not change the accumulation. This is shown only in
    mice; brain lipids have not been measured in patients.
  biological_processes:
  - preferred_term: lipophagy
    modifier: DECREASED
    term:
      id: GO:0061724
      label: lipophagy
  chemical_entities:
  - preferred_term: cholesteryl ester
    modifier: INCREASED
    term:
      id: CHEBI:17002
      label: cholesteryl ester
  evidence:
  - reference: PMID:36465123
    reference_title: "PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that CEs accumulate in the brain of PDZD8-deficient mice as a result of impaired lipophagy."
    explanation: Brain cholesteryl ester accumulation in PDZD8 knockout mice.
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36658656
      reference_title: "PDZD8-deficient mice manifest behavioral abnormalities related to emotion, cognition, and adaptation due to dyslipidemia in the brain."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "These results indicate that abnormal CE accumulation in the brain caused by PDZD8 deficiency affects emotion, cognition and adaptive behavior, and that PDZD8 plays an important role in the maintenance of brain function through lipid metabolism."
      explanation: In knockout mice the authors link brain cholesteryl ester accumulation to cognitive and behavioural deficits; a mouse inference not tested in patients.
- name: Impaired ER-Mitochondria Calcium Coupling
  conforms_to: "membrane_contact_site_dysfunction#Impaired Inter-Organelle Calcium Transfer"
  biological_scale: CELLULAR
  description: >-
    PDZD8 is needed for ER-mitochondria contacts. In cortical neurons its loss
    stops mitochondria taking up calcium released from the ER after synaptic
    stimulation, so cytosolic calcium rises higher in dendrites.
  biological_processes:
  - preferred_term: mitochondrial calcium ion homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0051560
      label: mitochondrial calcium ion homeostasis
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:29097544
    reference_title: "ER-mitochondria tethering by PDZD8 regulates Ca(2+) dynamics in mammalian neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In neurons, PDZD8 was required for calcium ion (Ca2+) uptake by mitochondria after synaptically induced Ca2+-release from ER and thereby regulated cytoplasmic Ca2+ dynamics."
    explanation: PDZD8 couples ER calcium release to mitochondrial uptake in neurons.
  downstream:
  - target: Hippocampal Synaptic Plasticity Deficit
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35227461
      reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "PDZD8 loss of function may have had similar effects following 3× TBS in Pdzd8tm1b hippocampal slices."
      explanation: The authors propose that loss of mitochondrial calcium buffering explains the reduced LTP in mutant slices; this was not tested.
- name: Impaired Neurite Outgrowth and Synapse Development
  biological_scale: CELLULAR
  description: >-
    PDZD8 depletion reduces neurite outgrowth in cultured cells, disrupts
    neuronal polarity, and in Drosophila blocks activity-dependent synaptic
    bouton formation. Pdzd8 mutant mice have increased dendritic spine
    density and reduced adult neurogenesis.
  biological_processes:
  - preferred_term: neuron projection development
    modifier: DECREASED
    term:
      id: GO:0031175
      label: neuron projection development
  - preferred_term: synapse organization
    modifier: ABNORMAL
    term:
      id: GO:0050808
      label: synapse organization
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:33912962
    reference_title: "PDZD8-mediated lipid transfer at contacts between the ER and late endosomes/lysosomes is required for neurite outgrowth."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functionally, PDZD8 is required for LE/lys positioning and neurite outgrowth, which is dependent on the lipid transfer activity of the SMP domain."
    explanation: PDZD8 is required for neurite outgrowth.
  - reference: PMID:40156832
    reference_title: "PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We find that PDZD8 is required for activity-dependent synaptic bouton formation in multiple paradigms."
    explanation: Synaptic bouton formation in Drosophila requires PDZD8.
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the brain, Pdzd8tm1b mice exhibit increased levels of accessory olfactory bulb volume, primary olfactory cortex volume, dendritic spine density, and ER stress- and mitochondrial fusion-related transcripts, as well as decreased levels of cerebellar nuclei volume and adult neurogenesis."
    explanation: Mutant mice have altered dendritic spine density and brain region volumes.
  downstream:
  - target: Hippocampal Synaptic Plasticity Deficit
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35227461
      reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Model organisms with manipulation of the orthologous gene replicate aspects of the human phenotype and suggest plausible pathophysiological mechanisms centered on disrupted brain development and synaptic function."
      explanation: The authors attribute the disorder to disrupted brain development and synaptic function; the step from neurite and synapse development to plasticity is inferred.
- name: Hippocampal Synaptic Plasticity Deficit
  biological_scale: TISSUE
  description: >-
    Pdzd8 mutant mice have reduced hippocampal long-term potentiation under
    maximal (3x theta burst) stimulation but not under submaximal protocols,
    together with impaired long-term spatial memory; fly knockdown impairs
    long-term courtship memory. Only the LTP reduction is bound as a process
    here; the memory deficits are organism-level behaviour and are carried by
    the intellectual disability phenotype. The authors read the cognitive
    impairment as a synaptopathy.
  biological_processes:
  - preferred_term: long-term synaptic potentiation
    modifier: DECREASED
    term:
      id: GO:0060291
      label: long-term synaptic potentiation
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits."
    explanation: Synaptic plasticity and spatial memory deficits in mutant mice.
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory."
    explanation: Long-term memory deficit in flies.
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35227461
      reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "In common with other neurodevelopmental disorders, the cognitive impairment associated with PDZD8 disruption is therefore likely to represent a synaptopathy resulting from synaptic dysfunction"
      explanation: The authors infer from the mouse plasticity deficit that the human cognitive impairment is a synaptopathy.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35227461
      reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Model organisms with manipulation of the orthologous gene replicate aspects of the human phenotype and suggest plausible pathophysiological mechanisms centered on disrupted brain development and synaptic function."
      explanation: Disrupted brain development and synaptic function are the proposed basis of the neurodevelopmental phenotype.
  - target: Autistic Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35227461
      reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings are thus consistent with accruing evidence that synaptic defects are a common denominator of ID and other neurodevelopmental conditions."
      explanation: Synaptic defects are proposed as the shared basis of the intellectual disability and autistic features; the link to autism is not tested directly.
phenotypes:
- name: Global Developmental Delay
  category: Neurodevelopmental
  frequency: OBLIGATE
  description: Developmental delay in all six reported individuals.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The discovery of a third family with IDDADF caused by biallelic disruption of PDZD8 permitted identification of a core clinical phenotype consisting of developmental delay, ID, autism, and facial dysmorphism."
    explanation: Developmental delay is part of the core phenotype.
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental Delay | Yes | Yes | 6/6"
    explanation: Present in 6 of 6 cases.
- name: Intellectual Disability
  category: Neurodevelopmental
  frequency: OBLIGATE
  description: >-
    Moderate to severe intellectual disability in all six; severe in four.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual Disability | Yes (severe) | Yes (severe) | 6/6 (severe: 4/6)"
    explanation: Present in 6 of 6, severe in 4.
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical examination revealed that all affected individuals have moderate to severe ID with autistic features, myopathy, and facial dysmorphism"
    explanation: Moderate to severe ID in family A.
- name: Autistic Behavior
  category: Behavioral
  frequency: OBLIGATE
  description: >-
    Autistic behaviour in all six; autism spectrum disorder diagnosed in
    five. Reported features include echolalia, jumping, hand flapping and
    lack of eye contact.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our finding that the Pdzd8tm1b mouse model and all six known cases of IDDADF exhibit autistic behavior, with ASD diagnosed in five cases, identifies this trait as a common outcome of biallelic disruption of PDZD8 in humans and mice."
    explanation: Autistic behaviour in all six cases, ASD in five.
- name: Motor Stereotypy
  category: Behavioral
  description: >-
    Hand flapping and jumping were described in one child; mutant mice show
    repetitive hindlimb jumping.
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild autistic features (echolalia, jumping, hand flapping, lack of eye contact)"
    explanation: Hand flapping and jumping in the family B proband.
- name: Echolalia
  category: Behavioral
  description: Echolalia in the family B proband.
  phenotype_term:
    preferred_term: Echolalia
    term:
      id: HP:0010529
      label: Echolalia
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild autistic features (echolalia, jumping, hand flapping, lack of eye contact)"
    explanation: Echolalia in the family B proband.
- name: Attention Deficit Hyperactivity Disorder
  category: Behavioral
  frequency: FREQUENT
  description: ADHD in two of six individuals.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ADHD | No | No | 2/6"
    explanation: Present in 2 of 6 cases.
- name: Absent Speech
  category: Neurodevelopmental
  description: >-
    Both affected siblings in family C lack functional language; the family B
    proband had delayed speech.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuropsychological assessments revealed that both the index case (C.IV.1) and his affected sister (C.IV.2) have severe ASD, severe ID, and a lack of functional language"
    explanation: No functional language in both family C siblings.
- name: Facial Dysmorphism
  category: Craniofacial
  frequency: OBLIGATE
  description: >-
    Facial dysmorphism in all six, typically a myopathic or hypotonic face
    with orbital hypertelorism, malar flattening, an open mouth and a high
    palate.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial Dysmorphism | Yes | Yes | 6/6"
    explanation: Present in 6 of 6 cases.
- name: Hypertelorism
  category: Craniofacial
  frequency: FREQUENT
  description: Orbital hypertelorism in four of six (all of families A and B).
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orbital Hypertelorism | No | No | 4/6"
    explanation: Present in 4 of 6 cases.
- name: Malar Flattening
  category: Craniofacial
  description: Reported in family A and in both siblings of family C.
  phenotype_term:
    preferred_term: Malar flattening
    term:
      id: HP:0000272
      label: Malar flattening
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "facial dysmorphism (myopathic face with orbital hypertelorism, malar flattening, open mouth, and high-arched palate)"
    explanation: Malar flattening in family A.
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They present facial dysmorphism (hypotonic face, malar flattening, thin palpebral fissures, and open mouth)"
    explanation: Malar flattening in family C.
- name: Myopathic Facies
  category: Craniofacial
  description: Myopathic face in family A.
  phenotype_term:
    preferred_term: Myopathic facies
    term:
      id: HP:0002058
      label: Myopathic facies
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "facial dysmorphism (myopathic face with orbital hypertelorism, malar flattening, open mouth, and high-arched palate)"
    explanation: Myopathic face in family A.
- name: Facial Hypotonia
  category: Craniofacial
  description: Hypotonic face in both siblings of family C.
  phenotype_term:
    preferred_term: Facial hypotonia
    term:
      id: HP:0000297
      label: Facial hypotonia
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They present facial dysmorphism (hypotonic face, malar flattening, thin palpebral fissures, and open mouth)"
    explanation: Hypotonic face in family C.
- name: Open Mouth
  category: Craniofacial
  description: Open mouth in families A and C.
  phenotype_term:
    preferred_term: Open mouth
    term:
      id: HP:0000194
      label: Open mouth
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "facial dysmorphism (myopathic face with orbital hypertelorism, malar flattening, open mouth, and high-arched palate)"
    explanation: Open mouth in family A.
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They present facial dysmorphism (hypotonic face, malar flattening, thin palpebral fissures, and open mouth)"
    explanation: Open mouth in family C.
- name: High Palate
  category: Craniofacial
  description: High-arched palate in family A.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "facial dysmorphism (myopathic face with orbital hypertelorism, malar flattening, open mouth, and high-arched palate)"
    explanation: High-arched palate in family A.
- name: Narrow Palpebral Fissure
  category: Craniofacial
  description: Thin palpebral fissures in family C.
  phenotype_term:
    preferred_term: Narrow palpebral fissure
    term:
      id: HP:0045025
      label: Narrow palpebral fissure
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They present facial dysmorphism (hypotonic face, malar flattening, thin palpebral fissures, and open mouth)"
    explanation: Thin palpebral fissures in family C.
- name: Ptosis
  category: Craniofacial
  description: Bilateral ptosis in the family B proband.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysmorphic features (low-set ears with simple helix, bilateral ptosis)"
    explanation: Bilateral ptosis in family B.
- name: Muscle Weakness
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: >-
    Mild muscle weakness in five of six. Family A was described as having
    myopathy (both carrier parents also had mild myopathy); family C as mild
    myasthenia with a limited walking distance. A homozygous ANKRD2 missense
    variant in family A may contribute to the myopathy there.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myasthenia | Yes (mild) | Yes (mild) | 5/6 (mild: 3/6)"
    explanation: Present in 5 of 6 cases.
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, because ANKRD2 is upregulated in congenital myopathies (33), p.(R328W) homozygosity may contribute to myopathy in family A."
    explanation: A second homozygous variant may contribute to the muscle phenotype in family A.
- name: Seizure
  category: Neurological
  frequency: FREQUENT
  description: Epilepsy in three of six; generalized in the family C index case.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy | Yes | No | 3/6"
    explanation: Present in 3 of 6 cases.
- name: Cerebral White Matter Abnormality
  category: Neurological
  description: >-
    Cortico-subcortical frontal and parietal demyelinating lesions in one
    family C sibling and subcortical nonspecific gliotic lesions in the
    other.
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed cortico-subcortical frontal and parietal demyelinating lesions with mild cerebellar hemispheric atrophy in C.IV.1 (Fig. 1F, G) and subcortical aspecific gliotic lesions in C.IV.2."
    explanation: White matter lesions in both family C siblings.
- name: Cerebellar Atrophy
  category: Neurological
  description: Mild cerebellar hemispheric atrophy in the family C index case.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed cortico-subcortical frontal and parietal demyelinating lesions with mild cerebellar hemispheric atrophy in C.IV.1 (Fig. 1F, G) and subcortical aspecific gliotic lesions in C.IV.2."
    explanation: Mild cerebellar atrophy in C.IV.1.
- name: Hypoplasia of the Corpus Callosum
  category: Neurological
  description: >-
    Hypoplasia of the splenium in one family A individual; mutant mice have a
    relatively reduced corpus callosum.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain Scan Findings | ND | ND | Hypoplasia of splenium of corpus callosum | Normal"
    explanation: Splenial hypoplasia in A.IV.5.
- name: Myopia
  category: Ophthalmological
  frequency: FREQUENT
  description: Myopia in two of six.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myopia | No | No | 2/6"
    explanation: Present in 2 of 6 cases.
- name: Marfanoid Habitus
  category: Musculoskeletal
  frequency: FREQUENT
  description: Marfanoid habitus in two of six (family A).
  phenotype_term:
    preferred_term: Marfanoid habitus
    term:
      id: HP:0001519
      label: Disproportionate tall stature
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marfanoid Habitus | No | No | 2/6"
    explanation: Present in 2 of 6 cases.
- name: Short Stature
  category: Growth
  description: >-
    Proportionate short stature (height below -3 SD) without skeletal
    dysplasia in both family C siblings; mutant mice have reduced body size.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a proportional short stature, with a height more than three standard deviations below the mean for age and sex"
    explanation: Short stature in both family C siblings.
- name: Scoliosis
  category: Musculoskeletal
  frequency: FREQUENT
  description: Scoliosis in two of six.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scoliosis | Yes | No | 2/6"
    explanation: Present in 2 of 6 cases.
genetic:
- name: PDZD8
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PDZD8
    term:
      id: hgnc:26974
      label: PDZD8
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    No ClinGen gene-disease validity assertion was found for this pair. Three
    families with three different homozygous truncating variants support the
    association. gnomAD constraint metrics indicate PDZD8 is extremely
    intolerant of loss-of-function variation, yet heterozygous relatives do
    not have the syndrome.
  variants:
  - name: NM_173791.5:c.88C>T (p.Gln30Ter)
    type: nonsense
    variant_type: single nucleotide variant
    description: >-
      Homozygous in family C (Afghan origin, two affected siblings). Exon 1.
      One heterozygote in gnomAD v4.1.0.
    evidence:
    - reference: PMID:40016860
      reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "identified a homozygous nonsense variant in PDZD8 exon 1"
      explanation: Identity of the family C variant.
  - name: NM_173791.5:c.894C>G (p.Tyr298Ter)
    type: nonsense
    variant_type: single nucleotide variant
    description: Homozygous in family B (Emirati, one affected boy). Exon 2. Absent from gnomAD.
    evidence:
    - reference: PMID:35227461
      reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "revealed a homozygous nonsense variant in PDZD8 exon 2"
      explanation: Identity of the family B variant.
  - name: NM_173791.5:c.2197_2200del (p.Ser733Ter)
    type: frameshift
    variant_type: deletion
    description: >-
      Homozygous in family A (Omani, three affected siblings). A 4-bp deletion
      in the last exon introducing a frameshift and premature termination
      codon. Absent from gnomAD.
    evidence:
    - reference: PMID:35227461
      reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The PDZD8 c.2197_2200del variant deletes four base pairs in exon 5, introducing a frameshift and PTC (Figure 1C and Table 2) absent from gnomAD."
      explanation: Identity of the family A variant.
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum-anchored lipid transfer protein, showed cosegregation with syndromic ID in both families."
    explanation: First report linking PDZD8 to the disorder.
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual developmental disorder with autism and dysmorphic facies (IDDADF) is a rare syndromic intellectual disability (ID) caused by homozygous disruption of PDZD8 (PDZ domain-containing protein 8), an integral endoplasmic reticulum (ER) protein."
    explanation: Confirmation in a third family.
diagnosis:
- name: Exome Sequencing
  description: >-
    All three families were diagnosed by homozygosity mapping and whole-exome
    sequencing with segregation analysis. The core phenotype of
    developmental delay, intellectual disability, autism and facial
    dysmorphism is the clinical clue.
  diagnosis_term:
    preferred_term: exome sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygosity mapping, whole-exome sequencing, and cosegregation analysis were used to identify the PDZD8 variant responsible for IDDADF, including diagnoses of ASD, in consanguineous family C."
    explanation: Diagnostic route used in family C.
treatments:
- name: Antiseizure Medication
  description: >-
    The family C index case with generalized epilepsy was treated with
    valproic acid and levetiracetam. No disease-specific treatment exists.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40016860
    reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, C.IV.1 presents scoliosis and generalized epilepsy treated by valproic acid (VPA) and levetiracetam"
    explanation: Single-patient report of the treatment used; response is not described.
- name: Genetic Counseling
  description: >-
    Counseling and carrier screening for consanguineous families, as
    proposed by the defining study.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This knowledge will benefit affected families through genetic counseling and carrier screening and facilitate the genetic diagnosis of other patients."
    explanation: The authors recommend genetic counseling and carrier screening.
animal_models:
- name: Pdzd8tm1b mouse
  species: Mouse
  genotype: Pdzd8tm1b homozygous (exon 3 replaced by lacZ cassette; p.F333Nfs1*), C57BL/6NTac
  publication: PMID:35227461
  description: >-
    Homozygous mice have reduced preweaning viability, smaller body and
    brain size, spontaneous repetitive hindlimb jumping, impaired long-term
    spatial memory, reduced long-term potentiation after maximal
    stimulation, impaired social recognition and social odour
    discrimination, dark-phase hyperactivity and increased metabolic rate.
  modeled_mechanisms:
  - target: Hippocampal Synaptic Plasticity Deficit
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Reduced hippocampal LTP and impaired long-term spatial memory.
    limitations: >-
      The LTP deficit appears only with maximal 3x theta burst stimulation and
      not with submaximal protocols; spatial learning itself is intact.
    evidence:
    - reference: PMID:35227461
      reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits."
      explanation: The model shows the plasticity and memory deficits.
  - target: Impaired Neurite Outgrowth and Synapse Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: UNKNOWN
    model_scale: TISSUE
    description: Increased dendritic spine density and reduced adult neurogenesis in mutant brain.
    limitations: >-
      Spine density is increased rather than reduced, so the direction of the
      synaptic change differs from the reduced neurite outgrowth seen in
      cultured cells; neurite outgrowth itself was not measured in the mouse.
    evidence:
    - reference: PMID:40016860
      reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the brain, Pdzd8tm1b mice exhibit increased levels of accessory olfactory bulb volume, primary olfactory cortex volume, dendritic spine density, and ER stress- and mitochondrial fusion-related transcripts, as well as decreased levels of cerebellar nuclei volume and adult neurogenesis."
      explanation: Spine density and neurogenesis changes in the mutant mouse brain.
  - target: Autistic Behavior
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Repetitive jumping and impaired social recognition and social odour discrimination.
    limitations: >-
      Sociability itself is unaltered, and a second Pdzd8 null line on a
      different background showed no social deficit.
    evidence:
    - reference: PMID:40016860
      reference_title: "Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In addition to impairments in social recognition and social odor discrimination, Pdzd8tm1b mice exhibit increases in locomotor activity (dark phase only) and metabolic rate (both lights-on and dark phases), and decreased plasma triglyceride in males."
      explanation: Social recognition deficits in mutant mice.
- name: Drosophila PDZD8 knockdown
  species: Fruit fly
  genotype: RNAi knockdown of the PDZD8 ortholog
  publication: PMID:35227461
  description: Knockdown flies have impaired long-term courtship-based memory.
  modeled_mechanisms:
  - target: Hippocampal Synaptic Plasticity Deficit
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Long-term memory deficit.
    limitations: >-
      Invertebrate behavioural memory assay; no hippocampus and no synaptic
      plasticity measurement.
    evidence:
    - reference: PMID:35227461
      reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory."
      explanation: Long-term memory deficit in knockdown flies.
discussions:
- discussion_id: iddadf_nonneural_features
  prompt: >-
    Which PDZD8 function explains the muscle weakness, facial dysmorphism and
    short stature of IDDADF, and which of the two contact-site roles
    (ER-endolysosome lipid transfer or ER-mitochondria calcium coupling)
    drives the neurodevelopmental phenotype?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Muscle Weakness
  - phenotypes#Facial Dysmorphism
  - phenotypes#Short Stature
  - pathophysiology#Impaired ER-Mitochondria Calcium Coupling
  - pathophysiology#Impaired Endolysosome Maturation
  rationale: >-
    The mechanistic evidence comes from cultured cells, flies and mice; no
    patient cells have been studied, and PDZD8 protein is not detectable in
    blood. The mouse studies link the cognitive phenotype to synaptic
    plasticity and brain lipid accumulation but do not separate the
    endolysosomal and mitochondrial roles. No source cited here addresses
    the muscle, craniofacial or growth features, and in family A a second
    homozygous ANKRD2 variant may contribute to the myopathy.
  evidence:
  - reference: PMID:35227461
    reference_title: "PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lack of PDZD8 protein in human blood limits our ability to detect truncated PDZD8 proteins (31)."
    explanation: Patient protein studies have not been possible from blood.
notes: >-
  Six individuals in three consanguineous families are published
  (PMID:35227461, PMID:40016860). Frequencies are given as counts out of six
  where the 2025 report tabulates them. Single-patient findings not modelled
  here include congenital heart defect, cleft palate, amblyopia,
  obsessive-compulsive behaviour, aggression and insomnia. PDZD8 lies in the
  distal 10q deletion region, but heterozygous relatives in these families
  do not have the syndrome. No GeneReviews chapter was found.
📚

References & Deep Research

References

9
PMID:35227461
PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies.
No top-level findings curated for this source.
PMID:40016860
Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice.
No top-level findings curated for this source.
PMID:29097544
ER-mitochondria tethering by PDZD8 regulates Ca(2+) dynamics in mammalian neurons.
No top-level findings curated for this source.
PMID:31636202
PDZD8 mediates a Rab7-dependent interaction of the ER with late endosomes and lysosomes.
No top-level findings curated for this source.
PMID:32917905
Protrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation.
No top-level findings curated for this source.
PMID:33912962
PDZD8-mediated lipid transfer at contacts between the ER and late endosomes/lysosomes is required for neurite outgrowth.
No top-level findings curated for this source.
PMID:40156832
PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth.
No top-level findings curated for this source.
PMID:36465123
PDZD8-deficient mice accumulate cholesteryl esters in the brain as a result of impaired lipophagy.
No top-level findings curated for this source.
PMID:36658656
PDZD8-deficient mice manifest behavioral abnormalities related to emotion, cognition, and adaptation due to dyslipidemia in the brain.
No top-level findings curated for this source.

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)

Create: Intellectual Developmental Disorder With Autism And Dysmorphic Facies (PDZD8) · 2026-10-23T02:08:35Z · View source

New entry for IDDADF (MONDO:0859281), autosomal recessive syndromic intellectual disability from homozygous PDZD8 truncating variants. Clinical content from the two family reports (PMID:35227461 families A and B; PMID:40016860 family C and a six-patient table, whose counts give phenotype frequencies). Pathograph: PDZD8 loss of lipid transfer and ER-endosome / ER-mitochondria tethering activity leads to impaired endolysosome maturation (and brain cholesteryl ester accumulation via impaired lipophagy, mouse) and impaired ER-mitochondria calcium coupling; both feed neurite/synapse development and hippocampal synaptic plasticity deficits, which the authors link to ID, developmental delay and autistic behaviour (edges marked INDIRECT where the step is the authors' inference). Mechanism evidence is from cells, flies and mice; no patient cells have been studied, recorded as a knowledge gap. Deep research (claude_code) used as leads only. Validated with just validate, validate-terms, count-verified-snippets (70/70), check-entity-refs, check-causal-targets, check-duplicate-keys, gene-activity grounding against origin/main, and validate-disorders. preflight-dr not run (no local MONDO build).

Claude Code ▸
PDZD8-related intellectual developmental disorder with autism and dysmorphic facies (IDDADF): research report
claude-haiku-5-5, claude-opus-5-5 18 citations 2026-10-23T01:59:20.125991

I'm reading the two key PDZD8 papers from the repository's cache. Next I'll pull the family C clinical details, then write the report.

PubMed search access was denied. I'm checking the stub file, then running a web search for newer PDZD8 papers.

I have the clinical and model-organism data. Now I'm checking the suggested ontology terms against the repository's term caches so the report doesn't list identifiers from memory.

PDZD8-related intellectual developmental disorder with autism and dysmorphic facies (IDDADF): research report

Target: MONDO:0859281 · causal gene PDZD8 (hgnc:26974) · OMIM #620021 Prepared: 2026-10-23

How this report was built

  • Primary sources. Almost all of the content comes from the only two clinical papers on this disease. Both are already in this worktree's references_cache/ as full text:
  • PMID:35227461, Al-Amri et al., Biol Psychiatry 2022. Families A and B, plus fly and mouse models.
  • PMID:40016860, Pantiru et al., Mol Autism 2025. Family C, a six-patient summary table, and further mouse work.
  • No search for newer patients. Permission to use the PubMed search tool was denied, so I could not search PubMed for patient reports after 2025. A web search (PMC11866840, Springer, MedGen C5774206 mirror) found nothing beyond these three families. The count of six patients is the count as of the 2025 paper.
  • Ontology terms. Every HP, GO, CL, UBERON, NCIT and CHEBI identifier below was read from the repository's cache/<prefix>/terms.csv files. Where a term could not be found that way, I say so.
  • Unverified PMIDs. The basic cell-biology papers on PDZD8 are cited by the clinical papers, but I could not confirm their PMIDs. They are listed in §6 as leads to fetch.

⚠️ Easy disease to confuse. cache/mondo/terms.csv holds MONDO:0014017, "intellectual developmental disorder with autism and macrocephaly". That is a different disease. Do not bind it to this entry. MONDO:0859281 has no row in the MONDO cache yet, so just validate-terms will need to resolve it.

1. Disease information

Overview. IDDADF is an ultra-rare autosomal recessive form of intellectual disability that comes with other features (a "syndromic" ID). It is caused by homozygous premature termination codons (PTCs) in PDZD8. PDZD8 is a protein embedded in the endoplasmic reticulum (ER) membrane that transfers lipids between membranes and helps hold organelles together at contact sites.

"Intellectual developmental disorder with autism and dysmorphic facies (IDDADF; OMIM #620021) is a very rare syndromic ID caused by homozygous premature termination codons (PTCs) in PDZD8, encoding PDZ domain-containing protein 8 (PDZD8)" — PMID:40016860

Identifiers

Resource ID
MONDO MONDO:0859281 (parent in stub: MONDO:0003847 hereditary disease)
OMIM #620021
MedGen C5774206
Gene PDZD8 (formerly PDZK8), hgnc:26974, 10q25.3–q26.11, 5 exons, 1,154 aa; UniProt Q8NEN9
Orphanet / ICD-10 / ICD-11 / MeSH No disease-specific code found. It would fall under the general intellectual disability codes.

Synonyms. IDDADF; PDZD8-related syndromic intellectual disability.

Source of the data. All data are case-level: three consanguineous families, six affected people. There is no registry and no EHR-derived data.

2. Etiology

  • Cause. Biallelic (homozygous) loss-of-function PTC variants in PDZD8. In every family the variant was found by homozygosity mapping plus exome sequencing, and it segregated with the disease.
  • Genetic risk factors.
  • Parental consanguinity: 6/6 cases, all children of first-cousin parents.
  • Ancestry: Omani, Emirati and Afghan.
  • Possible second variant in family A. Family A is also homozygous for ANKRD2 c.982C>T p.(R328W). The authors think this variant is unlikely to cause the ID, but it "may contribute to myopathy in family A" (PMID:35227461). This matters when scoring the muscle phenotype.
  • Modifier, protective, environmental and gene-environment factors. None reported.

3. Phenotypes

Frequencies are taken from the six-patient table in PMID:40016860 (Table 1, column "Incidence in all IDDADF cases"), with the family A/B details from PMID:35227461 Table 1.

"permitted identification of a core clinical phenotype consisting of developmental delay, ID, autism, and facial dysmorphism" — PMID:40016860

Phenotype Frequency Notes HPO (cache-verified)
Developmental delay 6/6 Congenital or early-childhood onset HP:0001263 Global developmental delay
Intellectual disability 6/6 (severe 4/6, moderate 2/6) Stanford-Binet IQ testing in family C HP:0001249 not in cache. Severity-specific terms were not checked; look them up
Autism / autistic behavior 6/6 (formal ASD diagnosis 5/6) Diagnosed by DSM-5, CARS2 or ADOS-2 in family C. Family C has severe ASD HP:0000717 Autism; HP:0000729 Autistic behavior
Facial dysmorphism 6/6 See facial features below HP:0001999 Abnormal facial shape (coarse, so it needs a coarse_binding_basis if used)
Hypertelorism (widely spaced eyes) 4/6 Families A and B HP:0000316 Hypertelorism
Malar flattening (flat cheekbones) Family A (3) and family C (2) HP:0000272 Malar flattening
Open mouth Family A and family C HP:0000194 Open mouth
High-arched palate Family A HP:0000218 High palate
Myopathic / hypotonic face Families A and C HP:0002058 Myopathic facies; HP:0000338 Hypomimic face
Narrow ("thin") palpebral fissures Family C (2) HP:0045025 Narrow palpebral fissure
Myopathy / myasthenia (mild weakness) 5/6 (mild 3/6) Family C has a limited walking distance. Family A may be confounded by the ANKRD2 variant HP:0003198 Myopathy; HP:0001324 Muscle weakness
Epilepsy 3/6 Generalized epilepsy in C.IV.1, treated with valproate and levetiracetam. One family A patient is "controlled" HP:0001250 Seizure; HP:0002197 Generalized-onset seizure
Absent or delayed speech Family C: no functional language (2). Family B: delayed speech HP:0001344 Absent speech; HP:0000750 Delayed speech and language development
Echolalia, hand flapping, poor eye contact Family B (1) HP:0010529 Echolalia (no cache rows for the other two)
ADHD 2/6 HP:0007018 Attention deficit hyperactivity disorder
OCD 1/6 Not in cache
Insomnia 1/6 HP:0100785 Insomnia
Aggression 1/6 HP:0000718 Aggressive behavior
Short stature 2/6 Family C only, more than 3 SD below the mean and proportionate HP:0004322 Short stature; HP:0003510 Severe short stature
Marfanoid habitus 2/6 Not in cache
Scoliosis 2/6 HP:0002650 Scoliosis
Myopia 2/6 HP:0000545 Myopia
Amblyopia, astigmatism 1/6 each HP:0000646 Amblyopia; HP:0000483 Astigmatism
Ptosis (bilateral) 1/6 HP:0000508 Ptosis
Low-set ears with simple helix 1/6 HP:0000369 Low-set ears; HP:0020206 Simple ear
Cleft palate 1/6 HP:0000175 Cleft palate
Congenital heart defect 1/6 Type not specified HP:0001627 Abnormal heart morphology
Overlapping toes 1/6 HP:0001845 Overlapping toe
Hypoplasia of the splenium of the corpus callosum 1/6 Patient A.IV.5. B.IV.2's scan was normal HP:0002079 Hypoplasia of the corpus callosum
Demyelinating cortico-subcortical lesions; gliotic lesions 2/6 Family C HP:0002500 Abnormal cerebral white matter morphology; HP:0002171 Gliosis
Mild cerebellar hemispheric atrophy 1/6 HP:0001272 Cerebellar atrophy

Mode of inheritance: HP:0000007 Autosomal recessive inheritance.

Carriers in family A. Both parents had mild myopathy and reduced facial expression. The father and one unaffected brother had mild autistic features. The authors still conclude that "PDZD8 haploinsufficiency is unlikely to have a major impact" (PMID:35227461). In family C, all heterozygous relatives are asymptomatic.

Quality of life. No formal measures (EQ-5D, SF-36) have been reported. Severe ID, lack of functional language and severe ASD imply lifelong dependence.

4. Genetic and molecular information

All variants are on transcript NM_173791.5.

Family Ancestry Variant Exon gnomAD CADD Source
A (3 affected) Omani c.2197_2200del p.(S733*) (4-bp deletion causing a frameshift and PTC) 5 (last exon) absent 35 PMID:35227461
B (1 affected) Emirati c.894C>G p.(Y298*) 2 absent 37 PMID:35227461
C (2 affected) Afghan c.88C>T p.(Q30*), chr10-117375140-G-A (GRCh38) 1 6.29×10⁻⁷, no homozygotes (v4.1.0) 35.0 PMID:40016860

Origin and zygosity. All three variants are germline and homozygous.

Functional consequence. Loss of function is predicted for all three: - p.(Q30) and p.(Y298) are expected to trigger nonsense-mediated mRNA decay (NMD). - p.(S733*) sits in the last exon, so it may escape NMD. Even then, the resulting protein would lack the C1 and coiled-coil domains that bind Rab7 and the endosomal lipids PS and PI4P.

"If the p.(Q30*) mRNA transcript evades nonsense-mediated decay, it may be translated into a truncated, non-functional PDZD8 protein lacking 1,125 C-terminal amino acids (97.5%)" — PMID:40016860

Gene constraint.

"gnomAD control datasets list five other predicted loss-of-function variants in PDZD8, none homozygous, and constraint metrics indicate that PDZD8 is extremely intolerant to loss-of-function variation" — PMID:35227461

Variant classification. I did not check ClinVar or ClinGen, and no ClinGen gene-disease validity record is known. Leave gene_disease_validity absent.

Protein domains (PMID:35227461): - ER transmembrane domain (aa 2–24) - SMP lipid-binding domain (91–294) - PDZ domain (366–449) - Proline-rich region (551–626) - C1 domain (840–891) - Coiled-coil domain (1028–1063)

Chromosomal abnormalities. PDZD8 lies within the region sometimes lost in distal 10q deletion syndrome. The healthy heterozygous carriers argue against haploinsufficiency explaining that syndrome (PMID:35227461).

Epigenetics and modifier genes. None reported. ANKRD2 is a possible contributor to the muscle phenotype in family A only.

5. Environmental information

Not applicable. No environmental, lifestyle or infectious factors are known.

6. Mechanism and pathophysiology

Causal chain

  1. Biallelic PTC in PDZD8. This leads to loss of full-length PDZD8, through NMD or truncation.
  2. Demonstrated in mouse: full-length protein is absent in Pdzd8^tm1b^ brain (PMID:35227461).
  3. Inferred in humans: PDZD8 protein cannot be detected in blood.
  4. Loss of PDZD8 at ER contact sites. This impairs two things:
  5. (a) Lipid transfer from the ER to late endosomes and lysosomes, and therefore endosome maturation (branch A).
  6. (b) ER–mitochondria tethering, and therefore mitochondrial Ca²⁺ uptake after synaptically triggered Ca²⁺ release from the ER (branch B).
  7. Both roles come from cell-biology work cited in the clinical papers. Their role in the human disease is inferred.
  8. Branch A. Defective endosomal homeostasis leads to abnormal vacuoles and impaired neuronal integrity.
  9. Shown in cultured neurons; not studied in patients.
  10. Branch B. Mitochondria take up less Ca²⁺, which leads to higher cytosolic Ca²⁺ in dendrites and likely impairs synaptic Ca²⁺ buffering and ATP supply.
  11. The ATP effect is the authors' hypothesis (PMID:35227461, Discussion).
  12. Synaptic dysfunction. In mouse hippocampus there is reduced saturated LTP (long-term potentiation, the strengthening of synapses with use) after 3× theta-burst stimulation, lower paired-pulse facilitation, and increased dendritic spine density.
  13. These lead to long-term memory deficits in mouse (Barnes maze) and fly (48-hour courtship memory).
  14. Source: model organisms, PMID:35227461 and PMID:40016860.
  15. Altered brain development. In mouse, total brain volume is smaller; relative corpus callosum volume is lower and relative hippocampal volume higher; the accessory olfactory bulb and primary olfactory cortex are larger; the cerebellar nuclei are smaller; and adult neurogenesis is reduced.
  16. The mouse corpus callosum change mirrors the splenium hypoplasia in patient A.IV.5.
  17. Clinical outcome. Steps 5 and 6 lead to ID, autism/ASD, and impaired social recognition. The mouse shows social-recognition and social-odor-discrimination deficits and repetitive hindlimb jumping (a stereotypy).
  18. The authors frame the disorder as a synaptopathy (a disease of synapse function).
  19. The step from the mouse to patients is inferred.
  20. Parallel systemic branch. Loss of PDZD8 affects cell metabolism. The paper notes that AMPK phosphorylates PDZD8 at T527, which is needed for glutaminolysis during low glucose. In mice this leads to higher metabolic rate, low body weight, lower plasma triglyceride in males, and smaller body size.
  21. This may relate to the short stature in family C, but the link is inferred.
  22. Stress and organelle readouts. Mouse brain shows more ER-stress and mitochondrial-fusion transcripts (Atf4, Hspa5, Mfn1/2, Opa1 were measured).
  23. Measured at the mRNA level only, which the authors list as a limitation.
  24. The white-matter lesions in family C are unexplained. PDZD8 is expressed in oligodendrocytes, but no mechanism is shown.

"In neurons, depletion of PDZD8 has been shown to impair endosomal homeostasis (13), decrease the proximity of the ER and mitochondria (14), and decrease calcium ion (Ca2+) uptake by mitochondria following synaptic transmission–induced Ca2+ release from the ER (15)." — PMID:35227461

"the cognitive impairment associated with PDZD8 disruption is therefore likely to represent a synaptopathy resulting from synaptic dysfunction" — PMID:35227461

Suggested terms (cache-verified)

  • GO processes:
  • GO:0006869 lipid transport; GO:0120013 lipid transfer activity (molecular function)
  • GO:0007032 endosome organization; GO:0008333 endosome to lysosome transport
  • GO:0006851 mitochondrial calcium ion transmembrane transport
  • GO:0051480 regulation of cytosolic calcium ion concentration; GO:0055074 calcium ion homeostasis
  • GO:0060291 long-term synaptic potentiation (modifier DECREASED)
  • GO:0007613 memory; GO:0007611 learning or memory; GO:0050890 cognition
  • GO:0035176 social behavior
  • GO:0097061 dendritic spine organization; GO:0060996 dendritic spine development
  • GO:0022008 neurogenesis
  • GO:0034976 response to endoplasmic reticulum stress
  • GO:0008053 mitochondrial fusion
  • GO cellular components: GO:0005789 endoplasmic reticulum membrane; GO:0005770 late endosome.
  • The ER–mitochondria and ER–endosome membrane-contact-site terms are not in the cache. Look them up with OAK before binding.
  • CL: CL:0000540 neuron; CL:0000598 pyramidal neuron; CL:0000679 glutamatergic neuron; CL:0000617 GABAergic neuron; CL:0000128 oligodendrocyte.

Mechanism papers to fetch with just fetch-reference

These are cited as refs 13–15 in PMID:35227461. None are confirmed.

  • Hirabayashi et al., Science 2017, "ER-mitochondria tethering by PDZD8 regulates Ca²⁺ dynamics in mammalian neurons." Likely PMID:29097544 (SGD reference ID; yeastgenome, Polleux lab, PMC5818999). Confirm.
  • Elbaz-Alon et al., Nat Commun 2020, "PDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria" (PMC7486383, Springer, IUCC). PMID not confirmed; PMID:32917905 appears on the MIT gene page but is not tied to this paper.
  • Shirane et al., 2020, Protrudin and PDZD8 lipid extraction for endosome maturation. PMID not obtained.
  • AMPK–PDZD8 pT527 glutaminolysis paper. PMID not obtained.

7. Anatomical structures affected

  • Primary organ: the brain (UBERON:0000955). The nervous system is the main system involved.
  • Specific regions: corpus callosum (UBERON:0002336), cerebral white matter, and cerebellum (UBERON:0002037).
  • Hippocampus and olfactory bulb (UBERON:0002264) are affected in the mouse. The hippocampus term was not in the cache.
  • Secondary organs:
  • Skeletal muscle (myopathy)
  • Spine (scoliosis)
  • Face and palate
  • Eye (myopia, ptosis, amblyopia)
  • Heart (1 case)
  • Linear growth (short stature)
  • Subcellular: ER membrane, late endosome/lysosome, mitochondria, and the contact sites between them.
  • Laterality: facial and ocular features are bilateral (e.g. bilateral ptosis).

8. Temporal development

  • Onset: congenital or infantile. Developmental delay is present in all patients, who were assessed between ages 4 and 30.
  • Course: a fixed neurodevelopmental disorder. No regression has been reported.
  • Possible progressive features (open question): scoliosis was worse at age 18 than at 13 in C.IV.1. The demyelinating lesions in C.IV.1 raise the possibility of a progressive white-matter process. With no natural-history data, this remains unanswered.
  • Critical periods: PDZD8 expression is stable from 8 weeks after conception to age 23 (BrainSpan data), which suggests a role throughout neurodevelopment (PMID:35227461).

9. Inheritance and population

  • Inheritance: autosomal recessive. Penetrance in homozygotes is 6/6 within the three families.
  • Expressivity: variable. ID ranges from moderate to severe, epilepsy is present in 3/6, and the non-core features differ between families.
  • Prevalence: unknown, with 6 published cases in 3 families. Suggested prevalence_class: CASES_IN_LITERATURE with ULTRA_RARE.
  • Population factors: no founder variant is known; each family has its own variant. All families are consanguineous, from the Arabian Peninsula and Afghanistan.
  • Sex: 4 male, 2 female.
  • Not reported: anticipation, germline mosaicism, carrier frequency.

10. Diagnostics

  • Diagnosis is genetic: exome sequencing, combined with homozygosity mapping in consanguineous families. Confirmation and segregation testing use Sanger sequencing. Exome CNV analysis (ExomeDepth) excluded deletions in family C.
  • Clinical evaluation:
  • IQ: Stanford-Binet
  • Adaptive behavior: Vineland-II, PEP-3
  • Autism: CARS2 and ADOS-2 against DSM-5 criteria
  • Brain MRI
  • EEG where seizures occur
  • Spine radiographs
  • Ophthalmologic exam
  • Biomarkers: none. PDZD8 protein is not detectable in blood.
  • Differential diagnosis:
  • Other autosomal recessive syndromic ID/ASD genes in consanguineous populations
  • Congenital myopathies (myopathic face)
  • Distal 10q deletion syndrome
  • Disorders of the PDZD8 partners: ZFYVE27/protrudin (spastic paraplegia) and RAB7A (CMT2B)
  • Screening: no newborn screening. Carrier testing and cascade testing are possible in families with a known variant.

11. Outcome and prognosis

  • Survival and life expectancy: no data. The oldest reported patient is 30 years old.
  • Pregnancy losses: family B had two in-utero deaths, but it is unknown whether they relate to PDZD8. In mice, survival to weaning was 36–48% lower than expected.
  • Morbidity: lifelong ID; severe ASD in family C; epilepsy; limited mobility (walking distance) in family C.
  • Prognostic factors: none established.

12. Treatment

There is no disease-specific therapy. Care is supportive and treats symptoms.

Intervention Terms (cache-verified) Basis
Antiseizure medication Valproic acid CHEBI:39867; levetiracetam CHEBI:6437 / NCIT:C47581 as therapeutic_agent on Pharmacotherapy NCIT:C15986 C.IV.1 (PMID:40016860)
Speech-language therapy NCIT:C159273 General care for ID/ASD; not reported in these papers
Occupational therapy NCIT:C121351 General care for ID/ASD
Physical therapy (myopathy, scoliosis) NCIT:C15302 General care
Genetic counseling / carrier testing NCIT:C15240 Recommended in PMID:35227461
  • Experimental: the authors suggest that p.(Y298*) "is potentially amenable to novel nonsense suppression therapies" (PMID:35227461). This is speculative; no trials exist.
  • Pharmacogenomics, gene therapy, cell therapy, clinical trials: none.

13. Prevention

  • Primary prevention: genetic counseling, carrier testing, and prenatal or preimplantation diagnosis for families with a known variant. Carrier screening can be offered in consanguineous communities.
  • Tertiary prevention:
  • Seizure management
  • Scoliosis surveillance
  • Ophthalmologic follow-up
  • Cardiac evaluation, given the one case with a heart defect
  • Vaccines and public-health measures: not applicable.

14. Other species / natural disease

  • Natural disease: none reported. OMIA was not searched.
  • Orthologs:
  • Mouse Pdzd8: 1,147 aa, 87% amino-acid conservation with human.
  • Drosophila CG10362 (FBgn0030358): 24% identity, lacks the coiled-coil domain.
  • Yeast: the SGD reference at 29097544 suggests PDZD8 is studied as an analog of the yeast ERMES ER–mitochondria tethering complex. This is not verified here.

15. Model organisms

Model Genotype What it reproduces Limitations Source
Mouse Pdzd8^tm1b(EUCOMM)Wtsi^ (C57BL/6NTac) Exon-3 replaced by lacZ, giving p.F333Nfs1* (homozygous) Repetitive hindlimb jumping (stereotypy); less habituation; less anxiety-like behavior; impaired long-term spatial memory (Barnes probe); lower 3×TBS LTP and paired-pulse facilitation; brain-volume changes, including relative corpus callosum reduction; impaired social recognition and social odor discrimination; more dendritic spines; less adult neurogenesis; higher ER-stress and mitochondrial-fusion transcripts; hyperactivity in the dark phase; higher metabolic rate; low body weight and size; lower plasma triglyceride in males; reduced pre-weaning viability No facial-dysmorphism equivalent. Sociability itself is intact. Unbalanced sex groups in some experiments. ER-stress and mitochondrial markers measured as mRNA only PMID:35227461; PMID:40016860
Drosophila Act5C-Gal4 > UAS-CG10362-RNAi (VDRC v8317) Ubiquitous knockdown, about 56% transcript reduction Impaired long-term (48-hour) courtship memory; learning and short-term memory intact Low conservation with human; partial knockdown only PMID:35227461

"Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits." — PMID:35227461

"Our finding that the Pdzd8tm1b mouse model and all six known cases of IDDADF exhibit autistic behavior, with ASD diagnosed in five cases, identifies this trait as a common outcome of biallelic disruption of PDZD8 in humans and mice." — PMID:40016860

Resources: - Mouse: EMMA strain 14234 (MRC Harwell); IMPC phenotyping data at mousephenotype.org. - Fly: VDRC line v8317.

Notes for the curator

  • Evidence grading. Clinical rows are HUMAN_CLINICAL. Mouse and fly rows are MODEL_ORGANISM.
  • Background quotes. The mechanistic sentences quoted from the introductions of the two clinical papers are background citations. Mark them quote_role: BACKGROUND, or better, quote the primary cell-biology papers once they are fetched.
  • Myopathy. Consider a note on the myopathy phenotype because of the ANKRD2 variant in family A.
  • MONDO term. MONDO:0859281 is uncached; MONDO:0014017 is the wrong disease and must not be used.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 4
Quoted claims found in source 3
Quoted claims not found in source 1
References weighed for topical relevance 9
On topic 8
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMC:PMC7486383: "PDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria"
  • closest text in source: "Endosome maturation depends on membrane contact sites (MCSs) formed between endoplasmic reticulum (ER) and endolysosomes (LyLEs)"

Term Validation

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

Outcome Count
Terms checked 78
Resolved 78
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 7
Terms named correctly 2
Terms named as a different term 0
Terms whose name is worth a second look 5

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:

  • UBERON:0000955 (1 mention) - the report calls it "Primary organ: the brain"; UBERON calls it brain**, and lists "the brain" among its other names
  • UBERON:0002336 (1 mention) - the report calls it "Specific regions: corpus callosum"; UBERON calls it corpus callosum
  • UBERON:0002264 (1 mention) - the report calls it "Hippocampus and olfactory bulb"; UBERON calls it olfactory bulb
  • NCIT:C15302 (1 mention) - the report calls it "Physical therapy (myopathy, scoliosis)"; NCIT calls it Physical Therapy
  • NCIT:C15240 (1 mention) - the report calls it "Genetic counseling / carrier testing"; NCIT calls it Genetic Counseling

Every term resolved, and every label the report gave matched.