16p11.2 Deletion Syndrome

Genetic MONDO:0012756 Pathograph 31 Show in embeddings browser hereditary disease chromosomal disorder

The proximal recurrent 16p11.2 BP4-BP5 deletion is a heterozygous copy-number loss of approximately 600 kb. Reduced dosage of multiple genes produces variable neurodevelopmental, neurologic, and metabolic manifestations. Speech and language impairment and motor coordination difficulties are prominent; most carriers do not meet criteria for intellectual disability. Autism and seizures affect a minority, and obesity commonly develops through childhood. The reciprocal duplication and the distal BP2-BP3 deletion are distinct genomic disorders.

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1
Inheritance
6
Pathophys.
25
Phenotypes
31
Pathograph
3
Genes
8
Medical Actions
1
Trials
1
Models
9
References
👪

Inheritance

1
Autosomal dominant recurrent microdeletion, usually de novo HP:0000006
A heterozygous deletion can be transmitted in an autosomal dominant manner. The one-in-two transmission risk follows from Mendelian segregation; it does not predict the severity or presence of any individual manifestation. Penetrance varies with phenotype and age, and expressivity is variable.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE De novo rate: Most probands in the clinical reviews. The 2012 pooled cohort reported 92/145 (64%) de novo events among carriers with available parental data; estimates vary with cohort ascertainment.
Show evidence (4 references)
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"The 16p11.2 recurrent deletion is de novo in most probands. Less commonly, the deletion is transmitted from a parent to a child in an autosomal dominant manner."
GeneReviews states the mode of inheritance and that transmission, when it occurs, is autosomal dominant.
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"The deletion is most often de novo but is inherited in approximately 7% of probands."
Provides the inherited fraction; this is not a population penetrance estimate.
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Penetrance is age-dependent and can be considered for each of the individual associated features (head size, brain volume, ASD, intellectual disability, language and coordination disorders, seizures, obesity, or congenital anomalies)."
Supports phenotype-specific and age-dependent penetrance rather than a single syndrome-wide estimate.
+ 1 more reference
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Pathophysiology

6
16p11.2 (BP4-BP5) Microdeletion
Loss of one copy of the proximal BP4-BP5 interval, approximately 600 kb, between homologous low-copy repeats.
Downstream
Reduced 16p11.2 Gene Dosage Loss of one copy of the interval genes reduces their dosage.
Show evidence (2 references)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"The recurrent ~600 kb copy number variant (CNV) at 16p11.2 BP4 and BP5 deletion is flanked by highly homologous blocks of low-copy repeats (Figure 1) and is one of the most frequent etiologies of neurodevelopmental disorders."
Defines the recurrent interval and flanking genomic architecture.
PMID:25564734 SUPPORT PRIMARY RESULT Human Clinical
"A pair of long direct genomic repeats (shown in orange) can mediate 0.6-Mb recurrent deletions."
The figure description supports repeat-mediated recurrent deletion.
Reduced 16p11.2 Gene Dosage
The deletion reduces copy number of multiple genes in the proximal interval. No single gene accounts for the complete syndrome, and gene-specific dosage sensitivity differs across manifestations.
Animal models
Mills and Dolmetsch 16p11.2 deletion mouse lines Mouse partially recapitulates Syntenic copy-number loss provides a model for downstream behavioral effects of multigene dosage reduction.
Downstream
Delayed Speech and Language Development The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Neurodevelopmental Delay The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Intellectual Disability The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Autism Spectrum Disorder The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Motor Coordination Difficulties The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Learning Difficulties The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Childhood Apraxia of Speech The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Attention Deficit Hyperactivity Disorder The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Macrocephaly The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Hypotonia The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Tremor The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
Hyperreflexia The deletion is associated with this manifestation; intervening gene-specific mechanisms are not established.
PRRT2 Dosage Reduction The deleted interval includes PRRT2, a candidate contributor to the infantile epilepsy phenotype.
TBX6 Dosage Reduction Loss of one TBX6 copy is part of the recurrent deletion.
Altered Satiety
Hyperphagia Hyperphagia occurs in deletion carriers; the responsible gene-to-appetite pathway is unresolved.
Delayed Gross Motor Development Delayed gross motor milestones occur in deletion carriers; the specific intervening mechanisms are unresolved.
Show evidence (1 reference)
PMID:36531974 SUPPORT PRIMARY RESULT Human Clinical
"Heterozygous pathogenic variants in PRRT2 are not clearly associated with ASD, and therefore, the CNV phenotype definitely extends beyond this single gene and is likely related to other genes contained in the deleted or duplicated segment."
Supports a multigene interpretation rather than attributing the complete syndrome to PRRT2.
PRRT2 Dosage Reduction
Mechanism confidence: Provisional
Loss of one PRRT2 copy is a candidate contributor to the self-limited infantile epilepsy phenotype within the multigene deletion syndrome.
PRRT2 hgnc:30500 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRRT2 (hgnc:30500). hgnc:30500 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Seizures Provisional contribution to the infantile epilepsy subset.
Show evidence (1 reference)
PMID:36531974 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"We can postulate that Se(F)IE syndrome seen in the deletion group is related, at least partly, to the loss-of-function of the PRRT2 gene."
The authors explicitly present PRRT2 attribution as a postulate, not a complete causal account.
TBX6 Dosage Reduction
The deletion removes one TBX6 allele. For congenital scoliosis, the dosage of the remaining allele modifies the effect of this null allele.
TBX6 hgnc:11605 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TBX6 (hgnc:11605). hgnc:11605 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
TBX6 Compound Dosage Deficiency This branch applies when the remaining TBX6 allele is hypomorphic.
Show evidence (1 reference)
PMID:25564734 SUPPORT PRIMARY RESULT Human Clinical
"However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis."
Loss of one copy alone does not explain penetrance of the vertebral phenotype.
TBX6 Compound Dosage Deficiency
A hypomorphic TBX6 allele in trans to the deletion further reduces effective TBX6 dosage. The T-C-A risk haplotype is a documented modifier of congenital scoliosis in deletion carriers.
TBX6 hgnc:11605 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TBX6 (hgnc:11605). hgnc:11605 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Vertebral Anomalies The pathway acts through disturbed embryonic vertebral formation; not every vertebral anomaly in deletion carriers is attributed to this genotype.
Show evidence (2 references)
PMID:25564734 SUPPORT PRIMARY RESULT In Vitro
"In vitro functional assays suggested that the risk haplotype is a hypomorphic allele."
Functional assays support reduced activity of the second allele.
PMID:25564734 SUPPORT PRIMARY RESULT Human Clinical
"The T-C-A risk haplotype was a significant risk factor for congenital scoliosis in series 3 (5 of 6 persons with congenital scoliosis vs. 5 of 30 persons without scoliosis, P=0.004 by Fisher’s exact test), which further supports the TBX6 compound inheritance model of the disorder."
The comparison is specifically among recurrent deletion carriers.
Altered Satiety
Satiety regulation is altered before overt obesity in some deletion carriers. The responsible gene-to-circuit pathway remains incompletely resolved.
Downstream
Obesity Reduced satiety contributes to excess intake and weight gain.
Show evidence (1 reference)
PMID:38050025 SUPPORT REVIEW SYNTHESIS Human Clinical
"Altered satiety presents prior to the onset of obesity (Maillard et al. 2016), serving as a flag to control portion size."
Identifies a metabolic process preceding obesity.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 16p11.2 Deletion Syndrome 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
Ear 1
Hearing Impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"Vertebral anomalies, hearing impairment, macrocephaly, and cardiovascular malformation have each been observed in some individuals."
GeneReviews establishes hearing impairment; the abstract does not quantify its frequency.
Eye 3
Deeply Set Eyes HP:0000490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deeply set eye (HP:0000490). HP:0000490 is a phenotype from the Human Phenotype Ontology.
Reported in the ocular case-literature review. Its percentages use 43 cases selected for documented eye findings and are not population frequencies for deletion carriers.
Show evidence (1 reference)
PMID:32373379 SUPPORT REVIEW SYNTHESIS Human Clinical
"From a systematic review of prior reported cases, the most common eye and ocular adnexa findings observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism."
Supports a recurring finding in the ocular case literature, without assigning its selected-case percentage as a syndrome-wide frequency.
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.
Reported in the ocular case-literature review. Its percentages use 43 cases selected for documented eye findings and are not population frequencies for deletion carriers.
Show evidence (1 reference)
PMID:32373379 SUPPORT REVIEW SYNTHESIS Human Clinical
"From a systematic review of prior reported cases, the most common eye and ocular adnexa findings observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism."
Supports a recurring finding in the ocular case literature, without assigning its selected-case percentage as a syndrome-wide frequency.
Hypertelorism 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.
Reported in the ocular case-literature review. Its percentages use 43 cases selected for documented eye findings and are not population frequencies for deletion carriers.
Show evidence (1 reference)
PMID:32373379 SUPPORT REVIEW SYNTHESIS Human Clinical
"From a systematic review of prior reported cases, the most common eye and ocular adnexa findings observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism."
Supports a recurring finding in the ocular case literature, without assigning its selected-case percentage as a syndrome-wide frequency.
Head and Neck 3
Macrocephaly OCCASIONAL HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Although head circumference is smaller at birth, there is an overall increase in head circumference by 2 years of age and macrocephaly (Z score ≥2) is present in 17% of carriers (Figure 2a) [10]."
Supports the 17% frequency and postnatal emergence of macrocephaly.
Abnormal Facial Shape FREQUENT HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Facial dysmorphism is usually subtle and does not form a readily recognizable diagnostic gestalt.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Facial dysmorphism are present in half of carriers, but the features are not striking or easily recognized."
Supports the frequency of nonspecific facial dysmorphism without inventing individual facial measurements or shapes.
Downslanted Palpebral Fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Reported in the ocular case-literature review. Its percentages use 43 cases selected for documented eye findings and are not population frequencies for deletion carriers.
Show evidence (1 reference)
PMID:32373379 SUPPORT REVIEW SYNTHESIS Human Clinical
"From a systematic review of prior reported cases, the most common eye and ocular adnexa findings observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism."
Supports a recurring finding in the ocular case literature, without assigning its selected-case percentage as a syndrome-wide frequency.
Integument 1
Sacral Dimple FREQUENT HP:0000960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sacral dimple (HP:0000960). HP:0000960 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Sacral dimples were noted in 34%, but without an associated tethered cord when assess by imaging."
Supports sacral dimples and explicitly does not establish associated tethered cord.
Musculoskeletal 2
Vertebral Anomalies OCCASIONAL Abnormal vertebral morphology HP:0003468 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal vertebral morphology (HP:0003468). HP:0003468 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"The most common anomaly is vertebral abnormalities (hemivertebrae or kyphoscoliosis affect ~20% of carriers) [10]."
Documents the vertebral abnormality spectrum in approximately one fifth of carriers.
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"We conducted a comprehensive chart review and in person examination by a child neurologist of 136 deletion carriers and identified features including symmetric hypotonia (50%), abnormal agility or clumsiness (47%), tremor (equivalent to essential tremor-25%) and increased reflexes/clonus (13%)..."
The review reports this finding in a neurologically examined cohort; the increased-reflexes frequency is grouped with clonus.
Nervous System 14
Delayed Speech and Language Development FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Deletion carriers have delays in early neurodevelopment that most specifically impair speech, phonology and language in 70%."
Speech, phonology, and language are impaired in 70% of deletion carriers.
Neurodevelopmental Delay VERY_FREQUENT HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
Developmental delay varies in severity and affected domains. This broad binding does not imply global delay in every carrier.
Show evidence (1 reference)
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"While most, if not all, individuals with the 16p11.2 recurrent deletion experience some degree of developmental delay, the severity varies significantly."
GeneReviews supports the very frequent developmental delay while emphasizing variable severity.
Intellectual Disability OCCASIONAL 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.
Intellectual disability occurs in a subset. A downward shift in the group IQ distribution is not equivalent to an intellectual-disability diagnosis in every carrier.
Show evidence (2 references)
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains."
Distinguishes intellectual disability from the more prevalent cognitive and learning difficulties.
PMID:23054248 SUPPORT PRIMARY RESULT Human Clinical
"Among carriers, 20% met DSM-IV-TR criteria for ID (65% mild FSIQ 55–70 and 35% moderate FSIQ 40–55)."
The primary study applied both IQ and adaptive-function criteria; intellectual disability affected a minority of the cognitively assessed carriers.
Autism Spectrum Disorder OCCASIONAL HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism spectrum disorder, annotated with Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
The frequency refers to diagnosed autism spectrum disorder. Autistic traits may also occur in carriers without an autism diagnosis.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Other common neurobehavioral conditions include motor coordination difficulties (60%) and autism (20-25%)."
Autism in 20-25% of deletion carriers.
Motor Coordination Difficulties FREQUENT Incoordination HP:0002311 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor coordination difficulties, annotated with Incoordination (HP:0002311). HP:0002311 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Other common neurobehavioral conditions include motor coordination difficulties (60%) and autism (20-25%)."
Motor-coordination difficulties in 60% of deletion carriers.
Seizures OCCASIONAL 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.
In the 2022 clinically ascertained cohort, 24% had at least one seizure and 18% met epilepsy criteria. Seizure types were heterogeneous; remission was common, but pharmacoresistant epilepsy occurred in a minority.
Show evidence (2 references)
PMID:36531974 SUPPORT PRIMARY RESULT Human Clinical
"Among 129 individuals with the 16p11.2 deletion, 31 (24%) had at least one seizure, including 23 (18%) who met criteria for epilepsy; 42% of them fit the phenotype of classic or atypical Self-limited (Familial) Infantile Epilepsy (Se(F)IE)."
Separates the seizure and epilepsy denominators; the full text identifies 13 of 31 seizure cases as classic or atypical infantile epilepsy.
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"Seizures are observed in approximately 25% of individuals with the recurrent deletion."
GeneReviews gives a concordant seizure estimate.
Learning Difficulties Specific learning disability HP:0001328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Specific learning disability (HP:0001328). HP:0001328 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains."
GeneReviews distinguishes learning disabilities from intellectual disability.
Childhood Apraxia of Speech FREQUENT Speech apraxia HP:0011098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Speech apraxia (HP:0011098). HP:0011098 is a phenotype from the Human Phenotype Ontology.
The 77% estimate applies to children; adult speech apraxia was reported in half.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Detailed examination of language strongly associates the 16p11.2 deletion with childhood apraxia of speech, which is seen in a majority (77%) of children and half of adults"
The age-stratified estimate supports frequent speech apraxia.
Attention Deficit Hyperactivity Disorder 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:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Taken with the ECHO and European 16p11.2 Consortium cohorts, disinhibited behavior, attention deficit hyperactivity disorder (ADHD) and ASD diagnoses were again the most common (20–25%) [8]."
The full-text review documents ADHD among recurrent diagnoses; no single ADHD frequency is assigned from this grouped statement.
Tremor OCCASIONAL HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"We conducted a comprehensive chart review and in person examination by a child neurologist of 136 deletion carriers and identified features including symmetric hypotonia (50%), abnormal agility or clumsiness (47%), tremor (equivalent to essential tremor-25%) and increased reflexes/clonus (13%)..."
The review reports this finding in a neurologically examined cohort; the increased-reflexes frequency is grouped with clonus.
Hyperreflexia HP:0001347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperreflexia (HP:0001347). HP:0001347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"We conducted a comprehensive chart review and in person examination by a child neurologist of 136 deletion carriers and identified features including symmetric hypotonia (50%), abnormal agility or clumsiness (47%), tremor (equivalent to essential tremor-25%) and increased reflexes/clonus (13%)..."
The review reports this finding in a neurologically examined cohort; the increased-reflexes frequency is grouped with clonus.
Chiari Type I Malformation OCCASIONAL HP:0007099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chiari type I malformation (HP:0007099). HP:0007099 is a phenotype from the Human Phenotype Ontology.
The 9% estimate comes from a clinical MRI cohort, not unselected carriers.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Indeed, we found that deletion carriers had a thicker corpus callosum compared to controls and that 30% of the deletion carriers had cerebellar tonsillar ectopia and 9% had radiologically defined Chiari I malformations [31]."
Distinguishes radiologically defined Chiari I malformation from the broader tonsillar-ectopia category.
Hyperphagia Polyphagia HP:0002591 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyphagia (HP:0002591). HP:0002591 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Among adults, ~75% are obese and among all adult obese patients 45% are morbidly obese, associated with hyperphagia [11]."
Documents hyperphagia accompanying obesity without assigning it the obesity frequency.
PMID:23054248 SUPPORT PRIMARY RESULT Human Clinical
"Hyperphagia was recorded (through parental questionnaires or reports) in all carriers (n=14) with obesity examined at the European site."
This is a selected obese subgroup of 14 carriers; it does not establish the prevalence of hyperphagia among all deletion carriers.
Delayed Gross Motor Development FREQUENT HP:0002194 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed gross motor development (HP:0002194). HP:0002194 is a phenotype from the Human Phenotype Ontology.
Reported in 32/85 (37.6%) European-cohort patients ascertained for developmental disorders or intellectual disability. This refers to delayed milestone acquisition, distinct from coordination difficulties.
Show evidence (1 reference)
PMID:23054248 SUPPORT PRIMARY RESULT Human Clinical
"Gross motor delay was reported in 37.6% of the patients (32/85 ascertained for DD/ID in the European cohorts),"
Provides the clinical-cohort denominator for delayed gross motor milestones.
Growth 1
Obesity FREQUENT HP:0001513 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obesity (HP:0001513). HP:0001513 is a phenotype from the Human Phenotype Ontology.
Frequency is age-dependent: the review estimates that 75% are obese by adulthood. Childhood BMI trajectories do not imply that all young children are obese.
Show evidence (2 references)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Obesity evolves throughout childhood and by adulthood 75% are obese."
About 75% of deletion carriers are obese by adulthood.
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"Obesity is a feature of this disorder and generally emerges in childhood; BMI in individuals with the 16p11.2 recurrent deletion is significantly higher than in the general population by age five years."
GeneReviews chapter independently establishes childhood-onset obesity as a core feature.
🧬

Genetic Associations

3
16p11.2 (BP4-BP5) deletion (Causal)
relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"The 16p11.2 BP4 and BP5 region, is a recurrent ∼600kb copy number variant (CNV), and deletions are one of the most frequent etiologies of neurodevelopmental disorders and autism spectrum disorder with an incidence of approximately 1/2000."
Defines the recurrent BP4-BP5 ~600 kb CNV as the causal lesion.
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis of 16p11.2 recurrent deletion is established by detection of a heterozygous ~593-kb recurrent deletion at the approximate position of chr16:29638676-30188531 in the reference genome (NCBI Build 38)."
GeneReviews gives the diagnostic interval and heterozygous dosage state of the recurrent deletion.
PRRT2
Gene: PRRT2 hgnc:30500 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRRT2 (hgnc:30500). hgnc:30500 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR
Show evidence (1 reference)
PMID:36531974 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"We can postulate that Se(F)IE syndrome seen in the deletion group is related, at least partly, to the loss-of-function of the PRRT2 gene."
The authors explicitly present PRRT2 attribution as a postulate, not a complete causal account.
TBX6
Gene: TBX6 hgnc:11605 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TBX6 (hgnc:11605). hgnc:11605 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER
Show evidence (1 reference)
PMID:25564734 SUPPORT PRIMARY RESULT Human Clinical
"The red bracket represents the deletion allele, and the nonreference alleles of rs2289292, rs3809624, and rs3809627 on the nondeletion chromosomes are shown in blue."
The figure legend locates the three risk-haplotype variants on the nondeleted chromosome; the carrier association is documented in the TBX6 dosage node.
💊

Medical Actions

8
Speech and Language Therapy
Action: Speech Language TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. NCIT:C159273
Platform: Behavioral / lifestyle
Individualized speech and language intervention addresses articulation, apraxia, receptive and expressive deficits.
Mechanism Target:
Delayed Speech and Language Development — Symptomatic treatment directed at this manifestation.
Childhood Apraxia of Speech — Symptomatic treatment directed at this manifestation.
Show evidence (1 reference)
PMID:38050025 SUPPORT REVIEW SYNTHESIS Other
"Evaluation and prompt treatment for speech and language disorders, including expressiveness, receptiveness, apraxia (Mei et al. 2018), auditory feedback, and motor control (Demopoulos et al. 2018), as well as social pragmatic communication disorders (Jiménez-Romero et al. 2022)."
The clinical review recommends prompt targeted speech treatment.
Developmental and Behavioral Support
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
Developmental assessment directs individualized educational and behavioral interventions.
Mechanism Target:
Neurodevelopmental Delay — Symptomatic treatment directed at this manifestation.
Learning Difficulties — Symptomatic treatment directed at this manifestation.
Autism Spectrum Disorder — Symptomatic treatment directed at this manifestation.
Show evidence (1 reference)
PMID:20301775 SUPPORT REVIEW SYNTHESIS Other
"Full developmental assessment, including neuropsychological testing by a clinical psychologist, is strongly suggested to establish neurodevelopmental needs and treatment recommendations."
GeneReviews recommends individualized assessment and treatment planning.
Physical Therapy
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Platform: Behavioral / lifestyle
Physical therapy addresses hypotonia and gross motor coordination difficulties.
Mechanism Target:
Hypotonia — Symptomatic treatment directed at this manifestation.
Motor Coordination Difficulties — Symptomatic treatment directed at this manifestation.
Show evidence (1 reference)
PMID:38050025 SUPPORT REVIEW SYNTHESIS Other
"Monitor for hypotonia and coordination disorders (Hinkley et al. 2019) with evaluation by occupational and physical therapy to address tone and coordination abnormalities."
The clinical review links rehabilitation to the motor manifestations.
Occupational Therapy
Action: Occupational TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Occupational Therapy (NCIT:C121351). NCIT:C121351 is a clinical intervention from the NCI Thesaurus. NCIT:C121351
Platform: Behavioral / lifestyle
Occupational therapy supports fine motor skills and adaptive function.
Mechanism Target:
Motor Coordination Difficulties — Symptomatic treatment directed at this manifestation.
Show evidence (1 reference)
PMID:38050025 SUPPORT REVIEW SYNTHESIS Other
"Monitor for hypotonia and coordination disorders (Hinkley et al. 2019) with evaluation by occupational and physical therapy to address tone and coordination abnormalities."
The clinical review supports occupational therapy for motor needs.
Weight Management
Action: Dietary InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. NCIT:C15447
Platform: Behavioral / lifestyle
Healthy eating, portion awareness, physical activity, and nutrition follow-up address childhood obesity risk.
Mechanism Target:
Obesity — Symptomatic treatment directed at this manifestation.
Hyperphagia — Symptomatic treatment directed at this manifestation.
Show evidence (2 references)
PMID:20301775 SUPPORT REVIEW SYNTHESIS Other
"Because of the high risk of obesity beginning in adolescence, encourage healthy eating habits with attention to portion size and an active lifestyle from a young age."
GeneReviews supports early diet and activity intervention.
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"Clinical follow-up data from adults suggests that the greatest medical challenges are obesity and related comorbidities that can be exacerbated by medications used to treat behavioral and psychiatric problems."
Supports attention to weight effects of psychiatric medications.
Antiseizure Therapy
Action: Anticonvulsant TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. NCIT:C64172
Agent: phenobarbital CHEBI:8069 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses phenobarbital (CHEBI:8069). CHEBI:8069 is a therapeutic agent from Chemical Entities of Biological Interest. carbamazepine CHEBI:3387 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carbamazepine (CHEBI:3387). CHEBI:3387 is a therapeutic agent from Chemical Entities of Biological Interest. oxcarbazepine CHEBI:7824 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses oxcarbazepine (CHEBI:7824). CHEBI:7824 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Neurologist-directed therapy is individualized to the seizure syndrome. Phenobarbital, carbamazepine, and oxcarbazepine showed favorable responses in the retrospective deletion cohort, especially self-limited infantile epilepsy; this was not a randomized drug comparison.
Mechanism Target:
Seizures — Symptomatic treatment directed at this manifestation.
Show evidence (1 reference)
PMID:36531974 SUPPORT PRIMARY RESULT Human Clinical
"Seizures responded favorably to phenobarbital, carbamazepine, and oxcarbazepine in the deletion group, specifically in the Se(F)IE, and to various antiseizure medications in the duplication group."
Provides syndrome-specific observational treatment evidence.
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. NCIT:C15240
Platform: Other
Offer parental testing, discuss variable expressivity and transmission, and explain prenatal and preimplantation testing options.
Show evidence (1 reference)
PMID:20301775 SUPPORT REVIEW SYNTHESIS Other
"Once a 16p11.2 recurrent deletion has been identified in a family member, prenatal and preimplantation genetic testing are possible. Interpretation of results from prenatal testing is challenging given the inherent difficulty in accurately predicting the phenotype."
GeneReviews supports reproductive testing options and prognostic uncertainty.
Arbaclofen (Investigational)
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: arbaclofen CHEBI:190735 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses arbaclofen (CHEBI:190735). CHEBI:190735 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A selective GABA-B receptor agonist evaluated in the phase II L16hthouse trial. The 2026 publication describes the study design and outcome measures, not a demonstrated clinical benefit.
Show evidence (3 references)
PMID:42080302 SUPPORT PRIMARY RESULT Human Clinical
"L16hthouse is the first randomized trial in 16p11.2 deletion syndrome and uses an array of novel outcome measures to assess potential benefit in this population."
Establishes investigational testing without asserting efficacy.
PMID:28984295 SUPPORT PRIMARY RESULT Model Organism
"In studies performed across two independent laboratories, we found that chronic activation of GABAB receptors improved performance on a series of cognitive and social tasks known to be impaired in two different 16p11.2 deletion mouse models."
Mouse behavioral improvement motivates clinical investigation; it does not establish efficacy in people.
PMID:28984295 SUPPORT PRIMARY RESULT Model Organism
"On the other hand, the finding that the hyperlocomotion and vocalization phenotypes were not improved by our treatment indicates that not all aberrant behavioral phenotypes associated with 16p11.2 deletion mice respond to this treatment."
Supports the stated limitation of selective rather than comprehensive behavioral rescue in mice.
🔬

Diagnosis

2
Chromosomal Microarray or Validated CNV Analysis (Heterozygous proximal BP4-BP5 deletion)
Identify the recurrent deletion by chromosomal microarray or sequencing with copy-number analysis. Targeted testing can evaluate relatives after the familial deletion has been established.
Show evidence (2 references)
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis of 16p11.2 recurrent deletion is established by detection of a heterozygous ~593-kb recurrent deletion at the approximate position of chr16:29638676-30188531 in the reference genome (NCBI Build 38)."
GeneReviews establishes the diagnostic interval and zygosity.
PMID:38050025 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis can be made by chromosome microarray or exome/genome sequencing, or with targeted quantitative polymerase chain reaction (qPCR) testing or fluorescence in situ hybridization (FISH)."
Supports copy-number testing strategies.
Developmental and Medical Surveillance
Assess development and behavior, growth and BMI, scoliosis, hearing, and seizure symptoms. Blood pressure and fasting glucose monitoring are recommended when obesity is present.
Show evidence (2 references)
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"Routine surveillance of growth parameters and calculation of BMI after age two years. Monitor developmental progress and educational needs and provide behavioral assessment at each visit."
Supports growth, developmental, and behavioral surveillance.
PMID:20301775 SUPPORT REVIEW SYNTHESIS Human Clinical
"Monitor those with seizures as clinically indicated and monitor for any new neurologic changes, scoliosis, or hearing loss. For those with obesity, monitor blood pressure and fasting blood glucose."
Supports symptom-directed neurologic surveillance and obesity-related monitoring.
🩻

Imaging Findings

3
Increased Brain Volume
Quantitative MRI studies show increased total brain and regional volumes in proximal deletion carriers.
Mri
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"The 16p11.2 deletion was associated with increased volumetric measures of brain structures (as well as total brain size and intracranial volume, ICV) (Figure 2b) [29]"
Describes quantitative brain-volume differences without assuming that they mediate all neurobehavioral findings.
Altered White Matter Microstructure
Diffusion tensor imaging shows widespread increased fractional anisotropy. Its relationship to conduction, synaptic transmission, and clinical deficits remains unresolved.
Mri
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"When considering brain white matter microstructural properties derived from diffusion tensor imaging (DTI), 16p11.2 deletion was associated with widespread increases in diffusion ‘fractional anisotropy’"
The review identifies increased fractional anisotropy. Its cellular basis and causal relationship to clinical deficits remain unresolved.
Cerebellar Tonsillar Ectopia
Cerebellar tonsillar ectopia was observed in 30% of a clinical MRI cohort, while 9% had radiologically defined Chiari I malformation. These overlapping findings should not be counted as independent phenotypes.
Mri
The OLS HP search for "cerebellar tonsillar ectopia" returned Chiari malformation; that binding would imply a diagnosis the broader imaging appearance alone does not establish.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Indeed, we found that deletion carriers had a thicker corpus callosum compared to controls and that 30% of the deletion carriers had cerebellar tonsillar ectopia and 9% had radiologically defined Chiari I malformations [31]."
Keeps tonsillar ectopia distinct from the more specific Chiari I diagnosis.
📊

Prevalence

1
General population
Point Prevalence 50.0 per 100,000 1–9 per 10,000
Approximately 1 in 2,000 people, equivalent to 50 per 100,000. The full-text review identifies this as general-population prevalence, not birth incidence.
Show evidence (1 reference)
PMID:33667823 SUPPORT REVIEW SYNTHESIS Human Clinical
"Reciprocal deletions and duplications are observed with a prevalence of approximately 1/2000 and 1/1100 in the general population, respectively [1]."
The first estimate applies to deletion carriers; the second to duplication carriers.
🔬

Clinical Trials

1
NCT04271332 PHASE_II UNKNOWN
L16hthouse evaluates arbaclofen against placebo in children with the proximal deletion, with an optional open-label extension. The ClinicalTrials.gov API reported overallStatus UNKNOWN on 2026-09-20; the last known status was ACTIVE_NOT_RECRUITING, last updated in May 2024. The 2026 publication reports design rather than efficacy results.
Target Phenotypes: Speech apraxia HP:0011098 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Speech apraxia (HP:0011098). HP:0011098 is a phenotype from the Human Phenotype Ontology. Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
clinicaltrials:NCT04271332 SUPPORT Other
"This Phase 2 study examines the safety, tolerability, and efficacy of arbaclofen in pediatric subjects with 16p11.2 deletion."
The registry establishes the investigational phase and disease scope.
PMID:42080302 SUPPORT PRIMARY RESULT Human Clinical
"Primary outcomes included speech articulation, measured by the Goldman Fristoe Test of Articulation 3 (GFTA-3)."
The trial-design report identifies the primary speech-articulation endpoint.
🐁

Animal Models

1
Mills and Dolmetsch 16p11.2 deletion mouse lines
Two independently generated lines show behavioral deficits and selective responses to chronic oral arbaclofen. Human language and intellectual disability are not directly measured by these behavioral assays.
Species
Mouse
Genotype
Heterozygous deletion of the mouse region syntenic to human proximal 16p11.2
Publication
PMID:28984295
Pathograph links
Reduced 16p11.2 Gene Dosage partially recapitulates fidelity: moderate observes: organism Syntenic copy-number loss provides a model for downstream behavioral effects of multigene dosage reduction.
Limitations: The lines differ in background and behavior. Novelty detection and social-interaction assays are proxies for selected human functions, not human speech or IQ; the mice have reduced body weight rather than the typical adult human obesity.
Show evidence (1 reference)
PMID:28984295 SUPPORT BACKGROUND Model Organism
"Studies in animal models where a single copy of the syntenic 16p11.2 region has been deleted have revealed morphological, behavioral, and electrophysiological abnormalities."
Supports partial modeling of dosage-associated phenotypes.
Show evidence (1 reference)
PMID:28984295 SUPPORT PRIMARY RESULT Model Organism
"Neither laboratory observed any improvement in the hyperlocomotion exhibited by the 16p11.2 df/+ mice with chronic R-baclofen administration."
Records an unrescued behavioral endpoint alongside the positive findings.
{ }

Source YAML

click to show 
name: 16p11.2 Deletion Syndrome
creation_date: '2026-08-22T00:00:00Z'
description: >-
  The proximal recurrent 16p11.2 BP4-BP5 deletion is a heterozygous copy-number loss of approximately
  600 kb. Reduced dosage of multiple genes produces variable neurodevelopmental, neurologic, and metabolic
  manifestations. Speech and language impairment and motor coordination difficulties are prominent; most
  carriers do not meet criteria for intellectual disability. Autism and seizures affect a minority, and
  obesity commonly develops through childhood. The reciprocal duplication and the distal BP2-BP3 deletion
  are distinct genomic disorders.
category: Genetic
synonyms:
- proximal 16p11.2 microdeletion syndrome
- 16p11.2 BP4-BP5 deletion
- 16p11.2 microdeletion syndrome
parents:
- hereditary disease
- chromosomal disorder
disease_term:
  preferred_term: proximal 16p11.2 microdeletion syndrome
  term:
    id: MONDO:0012756
    label: proximal 16p11.2 microdeletion syndrome
inheritance:
- name: Autosomal dominant recurrent microdeletion, usually de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: >-
    Most probands in the clinical reviews. The 2012 pooled cohort reported 92/145 (64%) de novo events
    among carriers with available parental data; estimates vary with cohort ascertainment.
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    A heterozygous deletion can be transmitted in an autosomal dominant manner. The one-in-two transmission
    risk follows from Mendelian segregation; it does not predict the severity or presence of any individual
    manifestation. Penetrance varies with phenotype and age, and expressivity is variable.
  evidence:
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 16p11.2 recurrent deletion is de novo in most probands. Less commonly, the deletion is transmitted
      from a parent to a child in an autosomal dominant manner.
    explanation: >-
      GeneReviews states the mode of inheritance and that transmission, when it occurs, is autosomal dominant.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The deletion is most often de novo but is inherited in approximately 7% of probands.
    explanation: >-
      Provides the inherited fraction; this is not a population penetrance estimate.
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Penetrance is age-dependent and can be considered for each of the individual associated features
      (head size, brain volume, ASD, intellectual disability, language and coordination disorders, seizures,
      obesity, or congenital anomalies).
    explanation: >-
      Supports phenotype-specific and age-dependent penetrance rather than a single syndrome-wide estimate.
  - reference: PMID:23054248
    reference_title: A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Globally, for participants with available parental data (51%), the deletion occurred de novo in
      92/145 cases (including two mosaic cases) (64%) and was inherited in the remaining cases (36%).
    explanation: >-
      The primary pooled cohort has a larger inherited fraction than the 2021 review summary. The ascertainment
      and parental-data denominator differ; neither fraction is a population penetrance estimate.
prevalence:
- population: General population
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 50.0
  notes: >-
    Approximately 1 in 2,000 people, equivalent to 50 per 100,000. The full-text review identifies this
    as general-population prevalence, not birth incidence.
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Reciprocal deletions and duplications are observed with a prevalence of approximately 1/2000 and
      1/1100 in the general population, respectively [1].
    explanation: >-
      The first estimate applies to deletion carriers; the second to duplication carriers.
pathophysiology:
- name: 16p11.2 (BP4-BP5) Microdeletion
  biological_scale: MOLECULAR
  description: >-
    Loss of one copy of the proximal BP4-BP5 interval, approximately 600 kb, between homologous low-copy
    repeats.
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The recurrent ~600 kb copy number variant (CNV) at 16p11.2 BP4 and BP5 deletion is flanked by highly
      homologous blocks of low-copy repeats (Figure 1) and is one of the most frequent etiologies of neurodevelopmental
      disorders.
    explanation: >-
      Defines the recurrent interval and flanking genomic architecture.
  - reference: PMID:25564734
    reference_title: TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A pair of long direct genomic repeats (shown in orange) can mediate 0.6-Mb recurrent deletions.
    explanation: >-
      The figure description supports repeat-mediated recurrent deletion.
  downstream:
  - target: Reduced 16p11.2 Gene Dosage
    causal_link_type: DIRECT
    description: Loss of one copy of the interval genes reduces their dosage.
    evidence:
    - reference: PMID:28984295
      reference_title: R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Caused by a single copy deletion of ~27 genes, 16p11.2 microdeletion syndrome is characterized
        by ID, impaired language, communication and socialization skills, and ASD.
      explanation: >-
        The introductory summary identifies multigene copy-number loss; it does not establish a precise
        gene count across annotation releases.
- name: Reduced 16p11.2 Gene Dosage
  biological_scale: MOLECULAR
  description: >-
    The deletion reduces copy number of multiple genes in the proximal interval. No single gene accounts
    for the complete syndrome, and gene-specific dosage sensitivity differs across manifestations.
  evidence:
  - reference: PMID:36531974
    reference_title: Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Heterozygous pathogenic variants in PRRT2 are not clearly associated with ASD, and therefore, the
      CNV phenotype definitely extends beyond this single gene and is likely related to other genes contained
      in the deleted or duplicated segment.
    explanation: >-
      Supports a multigene interpretation rather than attributing the complete syndrome to PRRT2.
  downstream:
  - target: Delayed Speech and Language Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:33667823
      reference_title: 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Deletion carriers have delays in early neurodevelopment that most specifically impair speech, phonology and language in 70%.
      explanation: Speech, phonology, and language are impaired in 70% of deletion carriers.
      quote_role: REVIEW_SYNTHESIS
  - target: Neurodevelopmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:20301775
      reference_title: 16p11.2 Recurrent Deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        While most, if not all, individuals with the 16p11.2 recurrent deletion experience some degree
        of developmental delay, the severity varies significantly.
      explanation: >-
        GeneReviews supports the very frequent developmental delay while emphasizing variable severity.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:20301775
      reference_title: 16p11.2 Recurrent Deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many
        have below average cognition and learning disabilities in both verbal and nonverbal domains.
      explanation: >-
        Distinguishes intellectual disability from the more prevalent cognitive and learning difficulties.
  - target: Autism Spectrum Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:33667823
      reference_title: 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Other common neurobehavioral conditions include motor coordination difficulties (60%) and autism (20-25%).
      explanation: Autism in 20-25% of deletion carriers.
      quote_role: REVIEW_SYNTHESIS
  - target: Motor Coordination Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:33667823
      reference_title: 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Other common neurobehavioral conditions include motor coordination difficulties (60%) and autism (20-25%).
      explanation: Motor-coordination difficulties in 60% of deletion carriers.
      quote_role: REVIEW_SYNTHESIS
  - target: Learning Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:20301775
      reference_title: 16p11.2 Recurrent Deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many
        have below average cognition and learning disabilities in both verbal and nonverbal domains.
      explanation: >-
        GeneReviews distinguishes learning disabilities from intellectual disability.
  - target: Childhood Apraxia of Speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:33667823
      reference_title: 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Detailed examination of language strongly associates the 16p11.2 deletion with childhood apraxia
        of speech, which is seen in a majority (77%) of children and half of adults
      explanation: >-
        The age-stratified estimate supports frequent speech apraxia.
  - target: Attention Deficit Hyperactivity Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:33667823
      reference_title: 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Taken with the ECHO and European 16p11.2 Consortium cohorts, disinhibited behavior, attention
        deficit hyperactivity disorder (ADHD) and ASD diagnoses were again the most common (20–25%) [8].
      explanation: >-
        The full-text review documents ADHD among recurrent diagnoses; no single ADHD frequency is assigned
        from this grouped statement.
  - target: Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:33667823
      reference_title: 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Although head circumference is smaller at birth, there is an overall increase in head circumference
        by 2 years of age and macrocephaly (Z score ≥2) is present in 17% of carriers (Figure 2a) [10].
      explanation: >-
        Supports the 17% frequency and postnatal emergence of macrocephaly.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:33667823
      reference_title: 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        We conducted a comprehensive chart review and in person examination by a child neurologist of
        136 deletion carriers and identified features including symmetric hypotonia (50%), abnormal agility
        or clumsiness (47%), tremor (equivalent to essential tremor-25%) and increased reflexes/clonus
        (13%) in deletion carriers [28].
      explanation: >-
        The review reports this finding in a neurologically examined cohort; the increased-reflexes frequency
        is grouped with clonus.
  - target: Tremor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:33667823
      reference_title: 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        We conducted a comprehensive chart review and in person examination by a child neurologist of
        136 deletion carriers and identified features including symmetric hypotonia (50%), abnormal agility
        or clumsiness (47%), tremor (equivalent to essential tremor-25%) and increased reflexes/clonus
        (13%) in deletion carriers [28].
      explanation: >-
        The review reports this finding in a neurologically examined cohort; the increased-reflexes frequency
        is grouped with clonus.
  - target: Hyperreflexia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The deletion is associated with this manifestation; intervening gene-specific mechanisms are not
      established.
    evidence:
    - reference: PMID:33667823
      reference_title: 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        We conducted a comprehensive chart review and in person examination by a child neurologist of
        136 deletion carriers and identified features including symmetric hypotonia (50%), abnormal agility
        or clumsiness (47%), tremor (equivalent to essential tremor-25%) and increased reflexes/clonus
        (13%) in deletion carriers [28].
      explanation: >-
        The review reports this finding in a neurologically examined cohort; the increased-reflexes frequency
        is grouped with clonus.
  - target: PRRT2 Dosage Reduction
    causal_link_type: DIRECT
    description: >-
      The deleted interval includes PRRT2, a candidate contributor to the infantile epilepsy phenotype.
    evidence:
    - reference: PMID:36531974
      reference_title: Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        There are at least 28 genes located in the 16p11.2 region. It remains unclear at this point, however,
        whether single genes are responsible for certain phenotypes. For a potential role in epilepsy,
        the most studied gene in this region is PRRT2.
      explanation: >-
        The cohort discussion locates PRRT2 within the recurrent interval; deletion of the interval therefore
        removes one copy.
  - target: TBX6 Dosage Reduction
    causal_link_type: DIRECT
    description: >-
      Loss of one TBX6 copy is part of the recurrent deletion.
    evidence:
    - reference: PMID:25564734
      reference_title: TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting
        TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations).
      explanation: >-
        Establishes deletion of TBX6 in affected carriers.
  - target: Altered Satiety
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38050025
      reference_title: Health supervision for children and adolescents with 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Altered satiety presents prior to the onset of obesity (Maillard et al. 2016), serving as a flag
        to control portion size.
      explanation: >-
        Links altered satiety to the metabolic phenotype while leaving the responsible proximal-interval
        genes unresolved.
  - target: Hyperphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hyperphagia occurs in deletion carriers; the responsible gene-to-appetite pathway is unresolved.
    evidence:
    - reference: PMID:33667823
      reference_title: 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Among adults, ~75% are obese and among all adult obese patients 45% are morbidly obese, associated
        with hyperphagia [11].
      explanation: >-
        Documents hyperphagia accompanying obesity without assigning it the obesity frequency.
  - target: Delayed Gross Motor Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Delayed gross motor milestones occur in deletion carriers; the specific intervening mechanisms are
      unresolved.
    evidence:
    - reference: PMID:23054248
      reference_title: A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Gross motor delay was reported in 37.6% of the patients (32/85 ascertained for DD/ID in the European
        cohorts),
      explanation: >-
        Provides the clinical-cohort denominator for delayed gross motor milestones.
- name: PRRT2 Dosage Reduction
  biological_scale: MOLECULAR
  description: >-
    Loss of one PRRT2 copy is a candidate contributor to the self-limited infantile epilepsy phenotype
    within the multigene deletion syndrome.
  mechanism_confidence: PROVISIONAL
  genes:
  - preferred_term: PRRT2
    term:
      id: hgnc:30500
      label: PRRT2
  evidence:
  - reference: PMID:36531974
    reference_title: Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: >-
      We can postulate that Se(F)IE syndrome seen in the deletion group is related, at least partly, to
      the loss-of-function of the PRRT2 gene.
    explanation: >-
      The authors explicitly present PRRT2 attribution as a postulate, not a complete causal account.
  downstream:
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Provisional contribution to the infantile epilepsy subset.
    evidence:
    - reference: PMID:36531974
      reference_title: Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        We can postulate that Se(F)IE syndrome seen in the deletion group is related, at least partly,
        to the loss-of-function of the PRRT2 gene.
      explanation: >-
        Supports provisional contribution to infantile epilepsy, not every seizure phenotype.
- name: TBX6 Dosage Reduction
  biological_scale: MOLECULAR
  description: >-
    The deletion removes one TBX6 allele. For congenital scoliosis, the dosage of the remaining allele
    modifies the effect of this null allele.
  genes:
  - preferred_term: TBX6
    term:
      id: hgnc:11605
      label: TBX6
  evidence:
  - reference: PMID:25564734
    reference_title: TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous
      TBX6 null mutation is insufficient to cause congenital scoliosis.
    explanation: >-
      Loss of one copy alone does not explain penetrance of the vertebral phenotype.
  downstream:
  - target: TBX6 Compound Dosage Deficiency
    causal_link_type: DIRECT
    description: >-
      This branch applies when the remaining TBX6 allele is hypomorphic.
    evidence:
    - reference: PMID:25564734
      reference_title: TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Replication studies involving additional persons with congenital scoliosis who carried a deletion
        affecting TBX6 confirmed this compound inheritance model.
      explanation: >-
        Supports the interaction of the deletion with the remaining hypomorphic allele.
- name: TBX6 Compound Dosage Deficiency
  biological_scale: MOLECULAR
  description: >-
    A hypomorphic TBX6 allele in trans to the deletion further reduces effective TBX6 dosage. The T-C-A
    risk haplotype is a documented modifier of congenital scoliosis in deletion carriers.
  genes:
  - preferred_term: TBX6
    term:
      id: hgnc:11605
      label: TBX6
  evidence:
  - reference: PMID:25564734
    reference_title: TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      In vitro functional assays suggested that the risk haplotype is a hypomorphic allele.
    explanation: >-
      Functional assays support reduced activity of the second allele.
  - reference: PMID:25564734
    reference_title: TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The T-C-A risk haplotype was a significant risk factor for congenital scoliosis in series 3 (5 of
      6 persons with congenital scoliosis vs. 5 of 30 persons without scoliosis, P=0.004 by Fisher’s exact
      test), which further supports the TBX6 compound inheritance model of the disorder.
    explanation: >-
      The comparison is specifically among recurrent deletion carriers.
  downstream:
  - target: Vertebral Anomalies
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The pathway acts through disturbed embryonic vertebral formation; not every vertebral anomaly in
      deletion carriers is attributed to this genotype.
    evidence:
    - reference: PMID:25564734
      reference_title: TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        All 23 persons with TBX6-associated congenital scoliosis had one or more hemivertebrae (Table
        1 and Fig. 2).
      explanation: >-
        Links TBX6 compound inheritance to vertebral formation defects; the cohort includes both deletion
        and sequence-null carriers.
- name: Altered Satiety
  biological_scale: ORGANISM
  description: >-
    Satiety regulation is altered before overt obesity in some deletion carriers. The responsible gene-to-circuit
    pathway remains incompletely resolved.
  evidence:
  - reference: PMID:38050025
    reference_title: Health supervision for children and adolescents with 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Altered satiety presents prior to the onset of obesity (Maillard et al. 2016), serving as a flag
      to control portion size.
    explanation: >-
      Identifies a metabolic process preceding obesity.
  downstream:
  - target: Obesity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reduced satiety contributes to excess intake and weight gain.
    evidence:
    - reference: PMID:38050025
      reference_title: Health supervision for children and adolescents with 16p11.2 deletion syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Altered satiety presents prior to the onset of obesity (Maillard et al. 2016), serving as a flag
        to control portion size.
      explanation: >-
        Provides temporal and clinical support for the proposed metabolic pathway.
phenotypes:
- category: Developmental
  name: Delayed Speech and Language Development
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Deletion carriers have delays in early neurodevelopment that most specifically impair speech, phonology and language in 70%.
    explanation: Speech, phonology, and language are impaired in 70% of deletion carriers.
    quote_role: REVIEW_SYNTHESIS
- category: Neurologic
  name: Neurodevelopmental Delay
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      While most, if not all, individuals with the 16p11.2 recurrent deletion experience some degree of
      developmental delay, the severity varies significantly.
    explanation: >-
      GeneReviews supports the very frequent developmental delay while emphasizing variable severity.
  notes: >-
    Developmental delay varies in severity and affected domains. This broad binding does not imply global
    delay in every carrier.
- category: Cognitive
  name: Intellectual Disability
  notes: >-
    Intellectual disability occurs in a subset. A downward shift in the group IQ distribution is not equivalent
    to an intellectual-disability diagnosis in every carrier.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many
      have below average cognition and learning disabilities in both verbal and nonverbal domains.
    explanation: >-
      Distinguishes intellectual disability from the more prevalent cognitive and learning difficulties.
  - reference: PMID:23054248
    reference_title: A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Among carriers, 20% met DSM-IV-TR criteria for ID (65% mild FSIQ 55–70 and 35% moderate FSIQ 40–55).
    explanation: >-
      The primary study applied both IQ and adaptive-function criteria; intellectual disability affected
      a minority of the cognitively assessed carriers.
  frequency: OCCASIONAL
- category: Behavioral
  name: Autism Spectrum Disorder
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Other common neurobehavioral conditions include motor coordination difficulties (60%) and autism (20-25%).
    explanation: Autism in 20-25% of deletion carriers.
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    The frequency refers to diagnosed autism spectrum disorder. Autistic traits may also occur in carriers
    without an autism diagnosis.
- category: Neurologic
  name: Motor Coordination Difficulties
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Motor coordination difficulties
    term:
      id: HP:0002311
      label: Incoordination
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Other common neurobehavioral conditions include motor coordination difficulties (60%) and autism (20-25%).
    explanation: Motor-coordination difficulties in 60% of deletion carriers.
    quote_role: REVIEW_SYNTHESIS
- category: Neurologic
  name: Seizures
  frequency: OCCASIONAL
  notes: >-
    In the 2022 clinically ascertained cohort, 24% had at least one seizure and 18% met epilepsy criteria.
    Seizure types were heterogeneous; remission was common, but pharmacoresistant epilepsy occurred in
    a minority.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:36531974
    reference_title: Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Among 129 individuals with the 16p11.2 deletion, 31 (24%) had at least one seizure, including 23
      (18%) who met criteria for epilepsy; 42% of them fit the phenotype of classic or atypical Self-limited
      (Familial) Infantile Epilepsy (Se(F)IE).
    explanation: >-
      Separates the seizure and epilepsy denominators; the full text identifies 13 of 31 seizure cases
      as classic or atypical infantile epilepsy.
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Seizures are observed in approximately 25% of individuals with the recurrent deletion.
    explanation: >-
      GeneReviews gives a concordant seizure estimate.
- category: Metabolic
  name: Obesity
  frequency: FREQUENT
  notes: >-
    Frequency is age-dependent: the review estimates that 75% are obese by adulthood. Childhood BMI trajectories
    do not imply that all young children are obese.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Obesity evolves throughout childhood and by adulthood 75% are obese.
    explanation: About 75% of deletion carriers are obese by adulthood.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Obesity is a feature of this disorder and generally emerges in childhood; BMI in individuals with the 16p11.2 recurrent deletion is significantly higher than in the general population by age five years.
    explanation: GeneReviews chapter independently establishes childhood-onset obesity as a core feature.
    quote_role: REVIEW_SYNTHESIS
- name: Learning Difficulties
  category: Cognitive
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many
      have below average cognition and learning disabilities in both verbal and nonverbal domains.
    explanation: >-
      GeneReviews distinguishes learning disabilities from intellectual disability.
- name: Childhood Apraxia of Speech
  category: Neurologic
  phenotype_term:
    preferred_term: Speech apraxia
    term:
      id: HP:0011098
      label: Speech apraxia
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Detailed examination of language strongly associates the 16p11.2 deletion with childhood apraxia
      of speech, which is seen in a majority (77%) of children and half of adults
    explanation: >-
      The age-stratified estimate supports frequent speech apraxia.
  frequency: FREQUENT
  notes: >-
    The 77% estimate applies to children; adult speech apraxia was reported in half.
- name: Attention Deficit Hyperactivity Disorder
  category: Behavioral
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Taken with the ECHO and European 16p11.2 Consortium cohorts, disinhibited behavior, attention deficit
      hyperactivity disorder (ADHD) and ASD diagnoses were again the most common (20–25%) [8].
    explanation: >-
      The full-text review documents ADHD among recurrent diagnoses; no single ADHD frequency is assigned
      from this grouped statement.
- name: Macrocephaly
  category: Neurologic
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Although head circumference is smaller at birth, there is an overall increase in head circumference
      by 2 years of age and macrocephaly (Z score ≥2) is present in 17% of carriers (Figure 2a) [10].
    explanation: >-
      Supports the 17% frequency and postnatal emergence of macrocephaly.
  frequency: OCCASIONAL
- name: Vertebral Anomalies
  category: Skeletal
  phenotype_term:
    preferred_term: Abnormal vertebral morphology
    term:
      id: HP:0003468
      label: Abnormal vertebral morphology
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most common anomaly is vertebral abnormalities (hemivertebrae or kyphoscoliosis affect ~20%
      of carriers) [10].
    explanation: >-
      Documents the vertebral abnormality spectrum in approximately one fifth of carriers.
  frequency: OCCASIONAL
- name: Hearing Impairment
  category: Auditory
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Vertebral anomalies, hearing impairment, macrocephaly, and cardiovascular malformation have each
      been observed in some individuals.
    explanation: >-
      GeneReviews establishes hearing impairment; the abstract does not quantify its frequency.
- name: Hypotonia
  category: Neurologic
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      We conducted a comprehensive chart review and in person examination by a child neurologist of 136
      deletion carriers and identified features including symmetric hypotonia (50%), abnormal agility
      or clumsiness (47%), tremor (equivalent to essential tremor-25%) and increased reflexes/clonus (13%)
      in deletion carriers [28].
    explanation: >-
      The review reports this finding in a neurologically examined cohort; the increased-reflexes frequency
      is grouped with clonus.
  frequency: FREQUENT
- name: Tremor
  category: Neurologic
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      We conducted a comprehensive chart review and in person examination by a child neurologist of 136
      deletion carriers and identified features including symmetric hypotonia (50%), abnormal agility
      or clumsiness (47%), tremor (equivalent to essential tremor-25%) and increased reflexes/clonus (13%)
      in deletion carriers [28].
    explanation: >-
      The review reports this finding in a neurologically examined cohort; the increased-reflexes frequency
      is grouped with clonus.
  frequency: OCCASIONAL
- name: Hyperreflexia
  category: Neurologic
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      We conducted a comprehensive chart review and in person examination by a child neurologist of 136
      deletion carriers and identified features including symmetric hypotonia (50%), abnormal agility
      or clumsiness (47%), tremor (equivalent to essential tremor-25%) and increased reflexes/clonus (13%)
      in deletion carriers [28].
    explanation: >-
      The review reports this finding in a neurologically examined cohort; the increased-reflexes frequency
      is grouped with clonus.
- name: Sacral Dimple
  category: Skeletal
  phenotype_term:
    preferred_term: Sacral dimple
    term:
      id: HP:0000960
      label: Sacral dimple
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Sacral dimples were noted in 34%, but without an associated tethered cord when assess by imaging.
    explanation: >-
      Supports sacral dimples and explicitly does not establish associated tethered cord.
  frequency: FREQUENT
- name: Chiari Type I Malformation
  category: Neurologic
  phenotype_term:
    preferred_term: Chiari type I malformation
    term:
      id: HP:0007099
      label: Chiari type I malformation
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Indeed, we found that deletion carriers had a thicker corpus callosum compared to controls and that
      30% of the deletion carriers had cerebellar tonsillar ectopia and 9% had radiologically defined
      Chiari I malformations [31].
    explanation: >-
      Distinguishes radiologically defined Chiari I malformation from the broader tonsillar-ectopia category.
  frequency: OCCASIONAL
  notes: >-
    The 9% estimate comes from a clinical MRI cohort, not unselected carriers.
- name: Hyperphagia
  category: Metabolic
  phenotype_term:
    preferred_term: Polyphagia
    term:
      id: HP:0002591
      label: Polyphagia
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Among adults, ~75% are obese and among all adult obese patients 45% are morbidly obese, associated
      with hyperphagia [11].
    explanation: >-
      Documents hyperphagia accompanying obesity without assigning it the obesity frequency.
  - reference: PMID:23054248
    reference_title: A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Hyperphagia was recorded (through parental questionnaires or reports) in all carriers (n=14) with
      obesity examined at the European site.
    explanation: >-
      This is a selected obese subgroup of 14 carriers; it does not establish the prevalence of hyperphagia
      among all deletion carriers.
- name: Abnormal Facial Shape
  category: Craniofacial
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  notes: >-
    Facial dysmorphism is usually subtle and does not form a readily recognizable diagnostic gestalt.
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Facial dysmorphism are present in half of carriers, but the features are not striking or easily
      recognized.
    explanation: >-
      Supports the frequency of nonspecific facial dysmorphism without inventing individual facial measurements
      or shapes.
- name: Delayed Gross Motor Development
  category: Developmental
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  notes: >-
    Reported in 32/85 (37.6%) European-cohort patients ascertained for developmental disorders or intellectual
    disability. This refers to delayed milestone acquisition, distinct from coordination difficulties.
  evidence:
  - reference: PMID:23054248
    reference_title: A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Gross motor delay was reported in 37.6% of the patients (32/85 ascertained for DD/ID in the European
      cohorts),
    explanation: >-
      Provides the clinical-cohort denominator for delayed gross motor milestones.
- name: Downslanted Palpebral Fissures
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  notes: >-
    Reported in the ocular case-literature review. Its percentages use 43 cases selected for documented
    eye findings and are not population frequencies for deletion carriers.
  evidence:
  - reference: PMID:32373379
    reference_title: 'Ocular Findings in the 16p11.2 Microdeletion Syndrome: A Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      From a systematic review of prior reported cases, the most common eye and ocular adnexa findings
      observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism.
    explanation: >-
      Supports a recurring finding in the ocular case literature, without assigning its selected-case
      percentage as a syndrome-wide frequency.
- name: Deeply Set Eyes
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Deeply set eye
    term:
      id: HP:0000490
      label: Deeply set eye
  notes: >-
    Reported in the ocular case-literature review. Its percentages use 43 cases selected for documented
    eye findings and are not population frequencies for deletion carriers.
  evidence:
  - reference: PMID:32373379
    reference_title: 'Ocular Findings in the 16p11.2 Microdeletion Syndrome: A Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      From a systematic review of prior reported cases, the most common eye and ocular adnexa findings
      observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism.
    explanation: >-
      Supports a recurring finding in the ocular case literature, without assigning its selected-case
      percentage as a syndrome-wide frequency.
- name: Ptosis
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  notes: >-
    Reported in the ocular case-literature review. Its percentages use 43 cases selected for documented
    eye findings and are not population frequencies for deletion carriers.
  evidence:
  - reference: PMID:32373379
    reference_title: 'Ocular Findings in the 16p11.2 Microdeletion Syndrome: A Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      From a systematic review of prior reported cases, the most common eye and ocular adnexa findings
      observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism.
    explanation: >-
      Supports a recurring finding in the ocular case literature, without assigning its selected-case
      percentage as a syndrome-wide frequency.
- name: Hypertelorism
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  notes: >-
    Reported in the ocular case-literature review. Its percentages use 43 cases selected for documented
    eye findings and are not population frequencies for deletion carriers.
  evidence:
  - reference: PMID:32373379
    reference_title: 'Ocular Findings in the 16p11.2 Microdeletion Syndrome: A Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      From a systematic review of prior reported cases, the most common eye and ocular adnexa findings
      observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism.
    explanation: >-
      Supports a recurring finding in the ocular case literature, without assigning its selected-case
      percentage as a syndrome-wide frequency.
genetic:
- name: 16p11.2 (BP4-BP5) deletion
  association: Causal
  notes: >-
    Heterozygous proximal BP4-BP5 copy-number loss. No single gene explains the complete syndrome; PRRT2
    and TBX6 have phenotype-specific contributions.
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The 16p11.2 BP4 and BP5 region, is a recurrent ∼600kb copy number variant (CNV), and deletions are one of the most frequent etiologies of neurodevelopmental disorders and autism spectrum disorder with an incidence of approximately 1/2000.
    explanation: Defines the recurrent BP4-BP5 ~600 kb CNV as the causal lesion.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The diagnosis of 16p11.2 recurrent deletion is established by detection of a heterozygous ~593-kb recurrent deletion at the approximate position of chr16:29638676-30188531 in the reference genome (NCBI Build 38).
    explanation: GeneReviews gives the diagnostic interval and heterozygous dosage state of the recurrent deletion.
    quote_role: REVIEW_SYNTHESIS
  relationship_type: CAUSATIVE
- name: PRRT2
  gene_term:
    preferred_term: PRRT2
    term:
      id: hgnc:30500
      label: PRRT2
  relationship_type: RISK_FACTOR
  notes: >-
    Deleted gene with a provisional contribution to self-limited infantile epilepsy; not a monogenic explanation
    of the full syndrome.
  evidence:
  - reference: PMID:36531974
    reference_title: Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: >-
      We can postulate that Se(F)IE syndrome seen in the deletion group is related, at least partly, to
      the loss-of-function of the PRRT2 gene.
    explanation: >-
      The authors explicitly present PRRT2 attribution as a postulate, not a complete causal account.
- name: TBX6
  gene_term:
    preferred_term: TBX6
    term:
      id: hgnc:11605
      label: TBX6
  relationship_type: MODIFIER
  notes: >-
    The nondeleted allele modifies congenital-scoliosis risk. The T-C-A haplotype comprises the nonreference
    alleles of rs2289292, rs3809624, and rs3809627; it is not required for the neurodevelopmental syndrome.
  evidence:
  - reference: PMID:25564734
    reference_title: TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The red bracket represents the deletion allele, and the nonreference alleles of rs2289292, rs3809624,
      and rs3809627 on the nondeletion chromosomes are shown in blue.
    explanation: >-
      The figure legend locates the three risk-haplotype variants on the nondeleted chromosome; the carrier
      association is documented in the TBX6 dosage node.
diagnosis:
- name: Chromosomal Microarray or Validated CNV Analysis
  presence: Heterozygous proximal BP4-BP5 deletion
  description: >-
    Identify the recurrent deletion by chromosomal microarray or sequencing with copy-number analysis.
    Targeted testing can evaluate relatives after the familial deletion has been established.
  evidence:
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of 16p11.2 recurrent deletion is established by detection of a heterozygous ~593-kb
      recurrent deletion at the approximate position of chr16:29638676-30188531 in the reference genome
      (NCBI Build 38).
    explanation: >-
      GeneReviews establishes the diagnostic interval and zygosity.
  - reference: PMID:38050025
    reference_title: Health supervision for children and adolescents with 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis can be made by chromosome microarray or exome/genome sequencing, or with targeted
      quantitative polymerase chain reaction (qPCR) testing or fluorescence in situ hybridization (FISH).
    explanation: >-
      Supports copy-number testing strategies.
- name: Developmental and Medical Surveillance
  description: >-
    Assess development and behavior, growth and BMI, scoliosis, hearing, and seizure symptoms. Blood pressure
    and fasting glucose monitoring are recommended when obesity is present.
  evidence:
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Routine surveillance of growth parameters and calculation of BMI after age two years. Monitor developmental
      progress and educational needs and provide behavioral assessment at each visit.
    explanation: >-
      Supports growth, developmental, and behavioral surveillance.
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Monitor those with seizures as clinically indicated and monitor for any new neurologic changes,
      scoliosis, or hearing loss. For those with obesity, monitor blood pressure and fasting blood glucose.
    explanation: >-
      Supports symptom-directed neurologic surveillance and obesity-related monitoring.
treatments:
- name: Speech and Language Therapy
  description: >-
    Individualized speech and language intervention addresses articulation, apraxia, receptive and expressive
    deficits.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: PMID:38050025
    reference_title: Health supervision for children and adolescents with 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Evaluation and prompt treatment for speech and language disorders, including expressiveness, receptiveness,
      apraxia (Mei et al. 2018), auditory feedback, and motor control (Demopoulos et al. 2018), as well
      as social pragmatic communication disorders (Jiménez-Romero et al. 2022).
    explanation: >-
      The clinical review recommends prompt targeted speech treatment.
  target_mechanisms:
  - target: Delayed Speech and Language Development
    description: >-
      Symptomatic treatment directed at this manifestation.
  - target: Childhood Apraxia of Speech
    description: >-
      Symptomatic treatment directed at this manifestation.
- name: Developmental and Behavioral Support
  description: >-
    Developmental assessment directs individualized educational and behavioral interventions.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Full developmental assessment, including neuropsychological testing by a clinical psychologist,
      is strongly suggested to establish neurodevelopmental needs and treatment recommendations.
    explanation: >-
      GeneReviews recommends individualized assessment and treatment planning.
  target_mechanisms:
  - target: Neurodevelopmental Delay
    description: >-
      Symptomatic treatment directed at this manifestation.
  - target: Learning Difficulties
    description: >-
      Symptomatic treatment directed at this manifestation.
  - target: Autism Spectrum Disorder
    description: >-
      Symptomatic treatment directed at this manifestation.
- name: Physical Therapy
  description: >-
    Physical therapy addresses hypotonia and gross motor coordination difficulties.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:38050025
    reference_title: Health supervision for children and adolescents with 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Monitor for hypotonia and coordination disorders (Hinkley et al. 2019) with evaluation by occupational
      and physical therapy to address tone and coordination abnormalities.
    explanation: >-
      The clinical review links rehabilitation to the motor manifestations.
  target_mechanisms:
  - target: Hypotonia
    description: >-
      Symptomatic treatment directed at this manifestation.
  - target: Motor Coordination Difficulties
    description: >-
      Symptomatic treatment directed at this manifestation.
- name: Occupational Therapy
  description: >-
    Occupational therapy supports fine motor skills and adaptive function.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Occupational Therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - reference: PMID:38050025
    reference_title: Health supervision for children and adolescents with 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Monitor for hypotonia and coordination disorders (Hinkley et al. 2019) with evaluation by occupational
      and physical therapy to address tone and coordination abnormalities.
    explanation: >-
      The clinical review supports occupational therapy for motor needs.
  target_mechanisms:
  - target: Motor Coordination Difficulties
    description: >-
      Symptomatic treatment directed at this manifestation.
- name: Weight Management
  description: >-
    Healthy eating, portion awareness, physical activity, and nutrition follow-up address childhood obesity
    risk.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Because of the high risk of obesity beginning in adolescence, encourage healthy eating habits with
      attention to portion size and an active lifestyle from a young age.
    explanation: >-
      GeneReviews supports early diet and activity intervention.
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Clinical follow-up data from adults suggests that the greatest medical challenges are obesity and
      related comorbidities that can be exacerbated by medications used to treat behavioral and psychiatric
      problems.
    explanation: >-
      Supports attention to weight effects of psychiatric medications.
  target_mechanisms:
  - target: Obesity
    description: >-
      Symptomatic treatment directed at this manifestation.
  - target: Hyperphagia
    description: >-
      Symptomatic treatment directed at this manifestation.
  notes: >-
    GeneReviews warns that behavioral or psychiatric medications may exacerbate obesity; medication selection
    should account for weight effects.
- name: Antiseizure Therapy
  description: >-
    Neurologist-directed therapy is individualized to the seizure syndrome. Phenobarbital, carbamazepine,
    and oxcarbazepine showed favorable responses in the retrospective deletion cohort, especially self-limited
    infantile epilepsy; this was not a randomized drug comparison.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: phenobarbital
      term:
        id: CHEBI:8069
        label: phenobarbital
    - preferred_term: carbamazepine
      term:
        id: CHEBI:3387
        label: carbamazepine
    - preferred_term: oxcarbazepine
      term:
        id: CHEBI:7824
        label: oxcarbazepine
  evidence:
  - reference: PMID:36531974
    reference_title: Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Seizures responded favorably to phenobarbital, carbamazepine, and oxcarbazepine in the deletion
      group, specifically in the Se(F)IE, and to various antiseizure medications in the duplication group.
    explanation: >-
      Provides syndrome-specific observational treatment evidence.
  target_mechanisms:
  - target: Seizures
    description: >-
      Symptomatic treatment directed at this manifestation.
- name: Genetic Counseling
  description: >-
    Offer parental testing, discuss variable expressivity and transmission, and explain prenatal and preimplantation
    testing options.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301775
    reference_title: 16p11.2 Recurrent Deletion.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Once a 16p11.2 recurrent deletion has been identified in a family member, prenatal and preimplantation
      genetic testing are possible. Interpretation of results from prenatal testing is challenging given
      the inherent difficulty in accurately predicting the phenotype.
    explanation: >-
      GeneReviews supports reproductive testing options and prognostic uncertainty.
- name: Arbaclofen (Investigational)
  description: >-
    A selective GABA-B receptor agonist evaluated in the phase II L16hthouse trial. The 2026 publication
    describes the study design and outcome measures, not a demonstrated clinical benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: arbaclofen
      term:
        id: CHEBI:190735
        label: Arbaclofen
  evidence:
  - reference: PMID:42080302
    reference_title: Rationale and study design for the first precision medicine randomized placebo-controlled trial in the 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      L16hthouse is the first randomized trial in 16p11.2 deletion syndrome and uses an array of novel
      outcome measures to assess potential benefit in this population.
    explanation: >-
      Establishes investigational testing without asserting efficacy.
  - reference: PMID:28984295
    reference_title: R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      In studies performed across two independent laboratories, we found that chronic activation of GABAB
      receptors improved performance on a series of cognitive and social tasks known to be impaired in
      two different 16p11.2 deletion mouse models.
    explanation: >-
      Mouse behavioral improvement motivates clinical investigation; it does not establish efficacy in
      people.
  - reference: PMID:28984295
    reference_title: R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      On the other hand, the finding that the hyperlocomotion and vocalization phenotypes were not improved
      by our treatment indicates that not all aberrant behavioral phenotypes associated with 16p11.2 deletion
      mice respond to this treatment.
    explanation: >-
      Supports the stated limitation of selective rather than comprehensive behavioral rescue in mice.
  notes: >-
    The mouse study did not improve every measured behavioral endpoint; hyperlocomotion and vocalization
    phenotypes were not rescued.
references:
- reference: PMID:20301775
  title: 16p11.2 Recurrent Deletion.
  tags:
  - GeneReviews
- reference: PMID:33667823
  title: 16p11.2 deletion syndrome.
- reference: PMID:36531974
  title: Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.
- reference: PMID:38050025
  title: Health supervision for children and adolescents with 16p11.2 deletion syndrome.
- reference: PMID:42080302
  title: Rationale and study design for the first precision medicine randomized placebo-controlled trial in the 16p11.2 deletion syndrome.
- reference: PMID:25564734
  title: TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
- reference: PMID:28984295
  title: R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice.
- reference: PMID:23054248
  title: A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.
- reference: PMID:32373379
  title: 'Ocular Findings in the 16p11.2 Microdeletion Syndrome: A Case Report and Literature Review.'
notes: >-
  This entry covers the proximal BP4-BP5 interval. It does not combine the distal SH2B1-containing deletion
  or the much larger 16p12.2-p11.2 deletion with this syndrome. Phenotype frequencies are cohort- and
  age-dependent. Most gene-to-neurobehavioral pathways remain unresolved; clinical associations are not
  evidence for a single universal causal gene.
clinical_trials:
- name: NCT04271332
  phase: PHASE_II
  status: UNKNOWN
  description: >-
    L16hthouse evaluates arbaclofen against placebo in children with the proximal deletion, with an optional
    open-label extension. The ClinicalTrials.gov API reported overallStatus UNKNOWN on 2026-09-20; the
    last known status was ACTIVE_NOT_RECRUITING, last updated in May 2024. The 2026 publication reports
    design rather than efficacy results.
  target_phenotypes:
  - preferred_term: Speech apraxia
    term:
      id: HP:0011098
      label: Speech apraxia
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: clinicaltrials:NCT04271332
    reference_title: An Exploratory, Randomized, Double-Blind, Placebo-Controlled and Open-label Extension Study of the Safety, Tolerability, and Efficacy of Arbaclofen in Subjects With 16p11.2 Deletion
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This Phase 2 study examines the safety, tolerability, and efficacy of arbaclofen in pediatric subjects
      with 16p11.2 deletion.
    explanation: >-
      The registry establishes the investigational phase and disease scope.
  - reference: PMID:42080302
    reference_title: Rationale and study design for the first precision medicine randomized placebo-controlled trial in the 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Primary outcomes included speech articulation, measured by the Goldman Fristoe Test of Articulation
      3 (GFTA-3).
    explanation: >-
      The trial-design report identifies the primary speech-articulation endpoint.
animal_models:
- name: Mills and Dolmetsch 16p11.2 deletion mouse lines
  species: Mouse
  genotype: Heterozygous deletion of the mouse region syntenic to human proximal 16p11.2
  description: >-
    Two independently generated lines show behavioral deficits and selective responses to chronic oral
    arbaclofen. Human language and intellectual disability are not directly measured by these behavioral
    assays.
  publication: PMID:28984295
  modeled_mechanisms:
  - target: Reduced 16p11.2 Gene Dosage
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Syntenic copy-number loss provides a model for downstream behavioral effects of multigene dosage
      reduction.
    limitations: >-
      The lines differ in background and behavior. Novelty detection and social-interaction assays are
      proxies for selected human functions, not human speech or IQ; the mice have reduced body weight
      rather than the typical adult human obesity.
    evidence:
    - reference: PMID:28984295
      reference_title: R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: >-
        Studies in animal models where a single copy of the syntenic 16p11.2 region has been deleted have
        revealed morphological, behavioral, and electrophysiological abnormalities.
      explanation: >-
        Supports partial modeling of dosage-associated phenotypes.
  evidence:
  - reference: PMID:28984295
    reference_title: R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Neither laboratory observed any improvement in the hyperlocomotion exhibited by the 16p11.2 df/+
      mice with chronic R-baclofen administration.
    explanation: >-
      Records an unrescued behavioral endpoint alongside the positive findings.
imaging_findings:
- name: Increased Brain Volume
  modality: MRI
  description: >-
    Quantitative MRI studies show increased total brain and regional volumes in proximal deletion carriers.
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The 16p11.2 deletion was associated with increased volumetric measures of brain structures (as well
      as total brain size and intracranial volume, ICV) (Figure 2b) [29]
    explanation: >-
      Describes quantitative brain-volume differences without assuming that they mediate all neurobehavioral
      findings.
- name: Altered White Matter Microstructure
  modality: MRI
  description: >-
    Diffusion tensor imaging shows widespread increased fractional anisotropy. Its relationship to conduction,
    synaptic transmission, and clinical deficits remains unresolved.
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      When considering brain white matter microstructural properties derived from diffusion tensor imaging
      (DTI), 16p11.2 deletion was associated with widespread increases in diffusion ‘fractional anisotropy’
    explanation: >-
      The review identifies increased fractional anisotropy. Its cellular basis and causal relationship
      to clinical deficits remain unresolved.
- name: Cerebellar Tonsillar Ectopia
  modality: MRI
  description: >-
    Cerebellar tonsillar ectopia was observed in 30% of a clinical MRI cohort, while 9% had radiologically
    defined Chiari I malformation. These overlapping findings should not be counted as independent phenotypes.
  evidence:
  - reference: PMID:33667823
    reference_title: 16p11.2 deletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Indeed, we found that deletion carriers had a thicker corpus callosum compared to controls and that
      30% of the deletion carriers had cerebellar tonsillar ectopia and 9% had radiologically defined
      Chiari I malformations [31].
    explanation: >-
      Keeps tonsillar ectopia distinct from the more specific Chiari I diagnosis.
  notes: >-
    The OLS HP search for "cerebellar tonsillar ectopia" returned Chiari malformation; that binding would
    imply a diagnosis the broader imaging appearance alone does not establish.
review_notes: >-
  Reviewed both originally cited sources, regenerated the Chung 2021 reference to full PMC text, and read
  the GeneReviews full chapter. New evidence also uses cached full texts of the 2022 seizure cohort, health-supervision
  review, TBX6 compound-inheritance study, and arbaclofen mouse study. The neighboring 16p12.2-p11.2 deep-research
  report concerns a larger deletion and was excluded. Hearing impairment, sacral dimples, nonspecific
  facial dysmorphism, and Chiari I remain without causal edges because the reviewed sources do not establish
  their intermediates. Imaging findings are retained as observations, without claiming that they causally
  explain language or cognition. The health-supervision review mentions probiotics from indirect preclinical
  work; this is not promoted to an established human treatment. The ocular baseline was expanded using
  the full case-literature review rather than treating a pooled eye/palpebral percentage as a population
  frequency. Its four recurring findings are modeled individually and remain without causal edges; the
  selected 43-case denominator and uncertain disease specificity are explicit. The full primary Zufferey
  cohort further qualifies inheritance, intellectual-disability and gross-motor estimates and hyperphagia
  ascertainment. That paper's 41.3% versus 12.5% obesity-associated macrocephaly comparison concerns the
  idiopathic-autism Simons Simplex Collection, so it is not imported as a deletion-carrier estimate.
📚

References & Deep Research

References

9
PMID:20301775
16p11.2 Recurrent Deletion.
No top-level findings curated for this source.
PMID:33667823
16p11.2 deletion syndrome.
No top-level findings curated for this source.
PMID:36531974
Clinical Characteristics of Seizures and Epilepsy in Individuals With Recurrent Deletions and Duplications in the 16p11.2 Region.
No top-level findings curated for this source.
PMID:38050025
Health supervision for children and adolescents with 16p11.2 deletion syndrome.
No top-level findings curated for this source.
PMID:42080302
Rationale and study design for the first precision medicine randomized placebo-controlled trial in the 16p11.2 deletion syndrome.
No top-level findings curated for this source.
PMID:25564734
TBX6 null variants and a common hypomorphic allele in congenital scoliosis.
No top-level findings curated for this source.
PMID:28984295
R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice.
No top-level findings curated for this source.
PMID:23054248
A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.
No top-level findings curated for this source.
PMID:32373379
Ocular Findings in the 16p11.2 Microdeletion Syndrome: A Case Report and Literature Review.
No top-level findings curated for this source.