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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Caused by homozygous or compound heterozygous loss-of-function variants in DCC; heterozygous carriers are either asymptomatic or may exhibit isolated congenital mirror movements or isolated agenesis of the corpus callosum with incomplete penetrance.

Autosomal recessive inheritance Penetrance: COMPLETE

Show evidence (3 references)

PMID:38585553 SUPPORT BACKGROUND Human Clinical

"Horizontal gaze palsy with progressive scoliosis-2 (HGPPS2, MIM 617542) with impaired intellectual development aka developmental split-brain syndrome is an ultra-rare congenital disorder caused by pathogenic biallelic variants in the deleted in colorectal cancer (DCC) gene."

Confirms autosomal recessive inheritance via biallelic pathogenic DCC variants.

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"HGPPS2 phenotype caused by biallelic DCC variants appears to be fully penetrant and shows a similar clinical presentation including developmental delay, intellectual disability, neuromuscular scoliosis, horizontal gaze palsy, agenesis of corpus callosum, and the absence of cerebral commissures."

Establishes complete penetrance of the full HGPPS2 syndrome in individuals with biallelic DCC loss-of-function variants.

PMID:33141514 SUPPORT PRIMARY RESULT Human Clinical

"Sanger Sequencing confirmed the presence of the novel homozygous mutation in all three patients; the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern."

Demonstrates autosomal recessive cosegregation in a multiplex consanguineous family.

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Mechanistic Hypotheses

1

Defective Spinal Commissural Interneuron Circuitry and Paraspinal Muscle Imbalance Driving Progressive Scoliosis

scoliosis_spinal_interneuron_hypothesis EMERGING

Evidence balance 2 support

Progressive childhood and adolescent scoliosis in HGPPS2 is hypothesized to result from defective midline crossing of spinal cord commissural interneurons (which coordinate left-right axial locomotor and postural motor networks in animal models of Netrin-1/DCC deficiency), leading to chronic paraspinal muscle activation imbalance during spinal growth.

Pathograph links

Pan-Neuraxis Commissural Axon Midline Crossing Failure -> Defective Spinal Commissural Interneuron Circuitry Midline crossing failure extends to spinal cord commissural interneurons required for bilateral axial motor coordination.

Defective Spinal Commissural Interneuron Circuitry -> Paraspinal Muscle Activation Imbalance Impaired bilateral coordination across spinal commissural interneuron circuits is hypothesized to cause asymmetric paraspinal muscle tone and activation.

Paraspinal Muscle Activation Imbalance -> Scoliosis Unbalanced paraspinal muscle forces across the growing vertebral column produce progressive childhood and adolescent thoracic and thoracolumbar scoliosis.

Show evidence (2 references)

PMID:28250456 SUPPORT BACKGROUND Model Organism

"We speculate that scoliosis may pertain to unbalanced paraspinal muscle activity due to defective spinal interneuron circuits (required for coordination of left-right locomotory patterns), since these circuits have been shown to be disrupted in Netrin-1 and DCC-deficient mice29,30."

Explicitly frames the link between defective spinal interneuron circuits, unbalanced paraspinal muscle activity, and progressive scoliosis as a mechanistic hypothesis supported by mouse knockout studies.

PMID:38585553 SUPPORT BACKGROUND Human Clinical

"The pathogenesis of progressive scoliosis in the disorder might arise from defective spinal commissural interneurons or paraspinal muscle activation imbalance"

Summarizes the proposed neurogenic mechanism linking spinal commissural interneuron defects and paraspinal muscle activation imbalance to progressive scoliosis.

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Pathophysiology

11

Loss of DCC Netrin-1 Receptor Function

Mechanism confidence: Established

Biallelic exon-skipping deletion, frameshift, intragenic duplication, or loss-of-function missense variants in DCC abolish or severely impair the deleted in colorectal carcinoma (DCC) transmembrane receptor protein. DCC normally binds extracellular netrin-1 (NTN1) and forms a molecular complex with ROBO3 to silence Slit-mediated repulsion and transduce attractive and long-range guidance cues required for developing commissural axons to approach and cross the anatomical midline of the central nervous system.

central nervous system neuron CL:0000117

DCC hgnc:2701

netrin-activated signaling pathway GO:0038007 commissural neuron axon guidance GO:0071679

netrin receptor activity GO:0005042

central nervous system UBERON:0001017

Downstream

Pan-Neuraxis Commissural Axon Midline Crossing Failure Absence of DCC-mediated netrin-1 attraction prevents pioneering commissural axons from crossing the midline across the forebrain, midbrain, hindbrain, and spinal cord.

Show evidence (3 references)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic..."

Establishes biallelic loss-of-function variants in the axon-guidance receptor gene DCC as the primary molecular defect.

PMID:29068161 SUPPORT REVIEW SYNTHESIS Other

"DCC is required for the transduction of NTN1-induced attractive and long-range repulsive signaling in the coordinated outgrowth and guidance of commissural axons that cross the anatomical midline of the body"

Details the role of DCC in transducing netrin-1 signaling to guide midline-crossing commissural axons.

PMID:28250456 SUPPORT BACKGROUND Model Organism

"Instead, Robo3 forms a direct molecular complex with DCC that silences repulsion from Slits33 (allowing developing neurons to approach) and enhances attraction to Netrins33,34."

Explains how DCC and ROBO3 interact molecularly in animal models to coordinate midline axon attraction and repulsion silencing.

Pan-Neuraxis Commissural Axon Midline Crossing Failure

Mechanism confidence: Established

Without functional DCC signaling, commissural axons fail to cross the anatomical midline at multiple levels of the central nervous system neuraxis, accompanied by broad disorganization of central nervous system white-matter architecture.

Defective Spinal Commissural Interneuron Circuitry and Paraspinal Muscle Imbalance Driving Progressive Scoliosis

central nervous system neuron CL:0000117

axon guidance GO:0007411 central nervous system projection neuron axonogenesis GO:0021952

central nervous system UBERON:0001017

Downstream

Forebrain Commissural Tract Agenesis Failure of pioneering cingulate and neocortical commissural axons to cross the telencephalic midline prevents formation of the corpus callosum, anterior commissure, and hippocampal commissure.

Non-Commissural Forebrain White-Matter Disorganization Pan-neuraxis DCC loss also disrupts organization of non-commissural forebrain white-matter projection tracts.

Abducens-to-Oculomotor Internuclear Crossing Failure Failure of internuclear commissural axons linking the abducens nucleus and contralateral oculomotor nucleus to cross the brainstem midline.

Midline Brainstem Clefting and Pontomedullary Hypoplasia Absence of crossing transverse pontine and medullary decussating fibers produces pontine and midbrain hypoplasia and a deep midline cleft across the brainstem.

Superior Cerebellar Peduncle Decussation Failure Failure of cerebellar efferent axons in the superior cerebellar peduncles to cross at the midbrain decussation (commissure of Wernekinck).

Corticospinal Tract Pyramidal Decussation Deficit Reduced midline crossing of descending corticospinal tract axons at the medullary pyramidal decussation.

Defective Spinal Commissural Interneuron Circuitry Midline crossing failure extends to spinal cord commissural interneurons required for bilateral axial motor coordination.

Show evidence (1 reference)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis."

Diffusion tractography and structural MRI confirm pan-neuraxis loss of commissural tracts.

Forebrain Commissural Tract Agenesis

Mechanism confidence: Established

Complete developmental absence of the major telencephalic and diencephalic commissures, including the corpus callosum, anterior commissure, and hippocampal commissure, eliminating direct interhemispheric commissural connectivity.

corpus callosum development GO:0022038 forebrain morphogenesis GO:0048853

corpus callosum UBERON:0002336 anterior commissure UBERON:0000935

Downstream

Longitudinal Probst Bundle Misrouting Callosal axons that fail to cross the interhemispheric fissure are diverted ipsilaterally into longitudinal Probst bundles along the lateral ventricles.

Agenesis of corpus callosum Failure of callosal commissural axons to cross the telencephalic midline directly manifests clinically and radiologically as complete agenesis of the corpus callosum.

Show evidence (1 reference)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"MR brain imaging revealed a number of abnormalities in the affected individuals (Supplementary Table 1, Fig. 1, Supplementary Fig. 1), including ACC and absence of the anterior (AC) and hippocampal commissures (HC)."

Confirms complete absence of the corpus callosum, anterior commissure, and hippocampal commissure on brain MRI.

Longitudinal Probst Bundle Misrouting

Mechanism confidence: Established

Uncrossed callosal axons accumulate ipsilaterally as longitudinally oriented Probst bundles running parallel to widely spaced lateral ventricles, producing the radiological racing car sign.

corpus callosum development GO:0022038

corpus callosum UBERON:0002336

Show evidence (1 reference)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"DCC(−/−) reconstructions did reveal characteristic, longitudinally misguided Probst bundles along the lateral ventricles (Supplementary Fig. 7b), a classic finding in some individuals with agenesis of the corpus callosum14."

Documents longitudinal Probst bundle formation along the lateral ventricles on diffusion tractography.

Non-Commissural Forebrain White-Matter Disorganization

Mechanism confidence: Provisional

Disorganization of non-commissural intrahemispheric and projection white-matter tracts in the forebrain accompanies complete commissural agenesis and impairs cognitive, behavioral, and neurodevelopmental maturation.

forebrain morphogenesis GO:0048853

central nervous system UBERON:0001017

Downstream

Intellectual disability Combined forebrain commissural agenesis and non-commissural forebrain white-matter disorganization impair cognitive development.

Global developmental delay Supratentorial and pan-neuraxis white-matter tract disorganization delays early motor and speech milestone acquisition.

Show evidence (1 reference)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Our patients’ cognitive deficits may at least partially be attributable to non-commissural forebrain white matter abnormalities as well."

Connects non-commissural forebrain white-matter tract abnormalities to cognitive and neurodevelopmental impairment in HGPPS2.

Abducens-to-Oculomotor Internuclear Crossing Failure

Mechanism confidence: Established

Loss of the internuclear commissural tract connecting the abducens nucleus (CN VI) across the brainstem midline to the contralateral medial oculomotor nucleus (CN III) via the medial longitudinal fasciculus abolishes conjugate horizontal eye movements while sparing vertical gaze.

hindbrain development GO:0030902

brainstem UBERON:0002298 pons UBERON:0000988 medial oculomotor nucleus UBERON:0002975

Downstream

Horizontal gaze palsy Absence of the crossed abducens-to-oculomotor internuclear pathway prevents coordinated abduction of one eye with adduction of the contralateral eye, causing congenital horizontal gaze palsy.

Show evidence (1 reference)

PMID:29068161 SUPPORT REVIEW SYNTHESIS Other

"These appear to include the decussation of the superior cerebellar peduncles (also referred to as the commissure of Wernekinck) that connects the cerebellum to the midbrain, and the commissural tract linking the lateral abducens and medial occulomotor nerves, required for conjugate horizontal..."

Identifies the specific internuclear abducens-to-oculomotor commissural tract disruption underlying conjugate horizontal gaze palsy.

Midline Brainstem Clefting and Pontomedullary Hypoplasia

Mechanism confidence: Established

Absence of transverse pontine fibers and decussating medullary tracts produces hypoplastic pons and midbrain structures, small middle cerebellar peduncles, and a deep midline cleft extending through the pons (split pons sign) and medulla oblongata (butterfly medulla).

hindbrain development GO:0030902

brainstem UBERON:0002298 pons UBERON:0000988 medulla oblongata UBERON:0001896

Downstream

Midline brainstem cleft Failure of pontine and medullary midline crossing fibers creates a deep dorsal and ventral midline cleft splitting the pons and shaping the medulla like a butterfly.

Hypoplasia of the brainstem Depletion of transverse pontine and decussating brainstem fiber bundles reduces the volume of the pons, midbrain, and middle cerebellar peduncles.

Show evidence (1 reference)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla (Supplementary Table 1, Supplementary Fig. 1b–g)."

Describes the characteristic brainstem hypoplasia, midline cleft, and butterfly-shaped medulla.

Superior Cerebellar Peduncle Decussation Failure

Mechanism confidence: Established

Absence of crossing fibers in the decussation of the superior cerebellar peduncles (commissure of Wernekinck), demonstrated by absence of the normal midbrain red dot sign on directional diffusion tensor color fractional anisotropy maps, impairs cerebellar efferent coordination.

hindbrain development GO:0030902

brainstem UBERON:0002298

Downstream

Ataxia Disrupted cerebellar-midbrain efferent decussation and hypoplastic cerebellar peduncles impair cerebellar coordination of gait, manifesting as broad-based ataxia.

Show evidence (1 reference)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Color FA maps from our DCC(−/−) patient showed a similar failure of SCPs to decussate, as evidenced by absence of the typical midbrain “red dot” sign16 (Fig. 3c). In the pons, our patient had small middle cerebellar peduncles and also lacked evidence of transverse pontine fibers (Fig. 3c), like..."

Tractography shows absence of superior cerebellar peduncle decussation and small middle cerebellar peduncles.

Corticospinal Tract Pyramidal Decussation Deficit

Mechanism confidence: Established

Reduced midline crossing of descending corticospinal tract projections at the pyramidal decussation in the lower medulla results in aberrant ipsilateral or bilateral motor cortex projection to spinal motor neurons in a subset of patients.

hindbrain development GO:0030902

medulla oblongata UBERON:0001896

Downstream

Mirror movements Unilateral voluntary motor commands transmitted via uncrossed corticospinal fibers produce involuntary synchronous contralateral mirror movements of the hands.

Show evidence (1 reference)

PMID:29068161 SUPPORT REVIEW SYNTHESIS Other

"Individuals with DSBS may also present with MMs, which are associated with the reduced midline crossing of descending CST projections at the pyramidal decussation"

Explains how reduced corticospinal tract decussation in the lower medulla leads to mirror movements.

Defective Spinal Commissural Interneuron Circuitry

Mechanism confidence: Hypothetical

Defective midline crossing of spinal cord commissural interneurons disrupts local spinal central pattern generator networks that coordinate left-right axial motor and proprioceptive signaling.

Defective Spinal Commissural Interneuron Circuitry and Paraspinal Muscle Imbalance Driving Progressive Scoliosis

spinal cord UBERON:0002240

Downstream

Paraspinal Muscle Activation Imbalance Impaired bilateral coordination across spinal commissural interneuron circuits is hypothesized to cause asymmetric paraspinal muscle tone and activation.

Show evidence (1 reference)

PMID:28250456 SUPPORT BACKGROUND Model Organism

"We speculate that scoliosis may pertain to unbalanced paraspinal muscle activity due to defective spinal interneuron circuits (required for coordination of left-right locomotory patterns), since these circuits have been shown to be disrupted in Netrin-1 and DCC-deficient mice29,30."

Proposes defective spinal commissural interneuron circuitry (demonstrated in Netrin-1 and DCC-deficient mice) as the upstream spinal mechanism in HGPPS2.

Paraspinal Muscle Activation Imbalance

Mechanism confidence: Hypothetical

Chronic asymmetrical activation of paraspinal musculature during childhood and adolescent axial skeletal growth drives progressive lateral curvature of the thoracic and thoracolumbar spine.

Defective Spinal Commissural Interneuron Circuitry and Paraspinal Muscle Imbalance Driving Progressive Scoliosis

vertebral column UBERON:0001130

Downstream

Scoliosis Unbalanced paraspinal muscle forces across the growing vertebral column produce progressive childhood and adolescent thoracic and thoracolumbar scoliosis.

Show evidence (1 reference)

PMID:38585553 SUPPORT BACKGROUND Human Clinical

"The pathogenesis of progressive scoliosis in the disorder might arise from defective spinal commissural interneurons or paraspinal muscle activation imbalance"

Summarizes the hypothesized role of paraspinal muscle activation imbalance in driving progressive scoliosis.

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Pathograph

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Phenotypes

11

Eye 1

Horizontal gaze palsy OBLIGATE Abnormal conjugate eye movement HP:0000549

Bound to HP:0000549 (Abnormal conjugate eye movement) rather than HP:0025590 (Horizontal supranuclear gaze palsy) because HPO restricts its horizontal gaze palsy term to supranuclear lesions, whereas horizontal gaze palsy in HGPPS2 results from internuclear brainstem midline crossing failure between the abducens and oculomotor nuclei.

Show evidence (2 references)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in..."

Establishes horizontal gaze palsy as an obligate hallmark present in 8/8 (100%) patients.

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"Her vertical eye movements were full and conjugated, but she lacked all horizontal eye movements, even horizontal optokinetic nystagmus. Her direct and consensual pupillary reflexes were normal. Cycloplegic refraction showed mild hyperopia."

Illustrates complete absence of horizontal eye movements with preserved vertical conjugate gaze.

Musculoskeletal 1

Scoliosis VERY_FREQUENT HP:0002650

Show evidence (2 references)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in..."

Establishes scoliosis in 7/8 (88%) reported patients.

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"She had a medical history of progressive scoliosis; at the age of 9 years, she had a thoracal scoliosis with a Cobb angle of 62° and a thoracolumbar scoliosis with a Cobb angle of 67°, which was operated. A month after the operation, she had a residual thoracal scoliosis with a Cobb angle of 15°..."

Documents severe progressive thoracic and thoracolumbar scoliosis requiring surgical correction.

Nervous System 8

Agenesis of corpus callosum OBLIGATE HP:0001274

Show evidence (2 references)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in..."

Confirms agenesis of the corpus callosum and absence of cerebral commissures in 7/7 (100%) imaged patients.

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"In posterior fossa, pons was split in midline, and medulla oblongata showed a butterfly shape because of large midline cleft throughout the brainstem (Fig. 3). In supratentorial space, total agenesis of corpus callosum and other commissural tracts was evident. Widely spaced lateral ventricles,..."

Details the characteristic supratentorial MRI appearance of total callosal agenesis and widely spaced lateral ventricles.

Midline brainstem cleft OBLIGATE HP:0033645

Show evidence (2 references)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla (Supplementary Table 1, Supplementary Fig. 1b–g)."

Documents the pathognomonic midline cleft throughout the brainstem and butterfly-shaped medulla.

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in..."

Confirms midline brainstem cleft in 7/7 (100%) patients who underwent neuroimaging.

Hypoplasia of the brainstem OBLIGATE HP:0002365

Show evidence (2 references)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla (Supplementary Table 1, Supplementary Fig. 1b–g)."

Confirms hypoplasia of the pons and midbrain structures across imaged patients.

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Color FA maps from our DCC(−/−) patient showed a similar failure of SCPs to decussate, as evidenced by absence of the typical midbrain “red dot” sign16 (Fig. 3c). In the pons, our patient had small middle cerebellar peduncles and also lacked evidence of transverse pontine fibers (Fig. 3c), like..."

Documents small middle cerebellar peduncles and absence of transverse pontine fibers contributing to pontine hypoplasia.

Global developmental delay FREQUENT HP:0001263

Show evidence (2 references)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"She has had significant failure to thrive, and her development has been remarkably delayed. She learned to roll from belly to back at the age of 2 years, crawl at the age of 5 years, and walk with mild support at the age of 8 years"

Illustrates profound motor milestone delay in an affected patient.

PMID:38516134 SUPPORT BACKGROUND Human Clinical

"HGPPS2 (OMIM1#617542) is caused by mutations of the DCC gene and distinguished from HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures."

Highlights global developmental delay as a key clinical feature distinguishing HGPPS2 from HGPPS1.

Intellectual disability FREQUENT HP:0001249

Show evidence (1 reference)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in..."

Documents intellectual disability in 5/8 (63%) reported patients.

Atypical behavior FREQUENT HP:0000708

Show evidence (2 references)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in..."

Reports behavioral problems in 3/5 (60%) evaluated patients.

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"She had poor eye contact and stereotypic repetitive wringing hand movements, but no mirror movements were noted. Her gait was broad based and ataxic."

Describes stereotypic repetitive hand-wringing and poor eye contact in an affected patient.

Mirror movements OCCASIONAL Bimanual synkinesia HP:0001335

Show evidence (2 references)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Furthermore, while the proband in Family 1 exhibited mirror movements, the affected individuals in Family 2 and 3 did not."

Provides primary clinical evidence that mirror movements occur in a minority (1 of 3 families in the original cohort) of biallelic DCC cases.

PMID:29068161 SUPPORT REVIEW SYNTHESIS Other

"Individuals with DSBS may also present with MMs, which are associated with the reduced midline crossing of descending CST projections at the pyramidal decussation [Jamuar, et al., 2017]."

Confirms that patients with developmental split-brain syndrome (HGPPS2) may occasionally present with congenital mirror movements.

Ataxia OCCASIONAL HP:0001251

Show evidence (1 reference)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"She had poor eye contact and stereotypic repetitive wringing hand movements, but no mirror movements were noted. Her gait was broad based and ataxic."

Documents a broad-based ataxic gait on neurological examination.

Growth 1

Short stature FREQUENT HP:0004322

Show evidence (1 reference)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in..."

Reports short stature in 3/5 (60%) evaluated patients.

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Genetic Associations

1

DCC (Causal Biallelic Loss-of-Function Variants)

Gene: DCC hgnc:2701 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic..."

Identifies biallelic loss-of-function mutations in DCC as the genetic cause of developmental split-brain syndrome / HGPPS2.

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"To date, including the case reported here, three different homozygous pathogenic frameshift variants, one homozygous missense variant, and an intragenic duplication in the DCC gene have been reported in 8 patients with the HGPPS2 syndrome."

Summarizes the allelic spectrum of pathogenic biallelic DCC variants across all 8 reported HGPPS2 patients.

Variants (5)

Homozygous 7682 bp exon 1 deletion (NM_005215.3 exon 1 skipping / p.Pro11Thrfs*15) Pathogenic

Gene: DCC hgnc:2701 deletion

Homozygous 7682 bp deletion (chr18:49867185-49874867del) removing 61 bp at the 3' end of coding exon 1 and 7.6 kb of intron 1 in DCC, causing complete skipping of exon 1 (which encodes the signal peptide and first immunoglobulin repeat) and acting as a functional null allele in two siblings from Family 1.

Show evidence (2 references)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"A series of PCR probes (Supplementary Fig. 4b) was used to localize the precise breakpoint (Supplementary Fig. 4c), revealing a 7682 bp deletion (Fig. 2d). This deletion removed the 3′ end of exon 1, containing 61 bp of DCC coding sequence (NM_005215.3) and 7.6 kb of intronic sequence (Fig. 2d)...."

Characterizes the homozygous 7682 bp deletion removing the 3' end of exon 1 and demonstrates complete exon 1 skipping in patient lymphoblasts.

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Exon 1 is the first coding exon and contains the signal peptide, required for correct orientational insertion into the membrane, and part of the first of DCC’s four immunoglobulin repeats, which adopt a horseshoe configuration critical for netrin-mediated guidance12. Disruption of these features..."

Demonstrates that loss of exon 1 disrupts the signal peptide and first immunoglobulin domain, producing a functional null allele.

NM_005215.3:c.788_794delTTTCTGG (p.Val263Alafs*36) Pathogenic

Gene: DCC hgnc:2701 frameshift variant

Homozygous 7-bp deletion in exon 4 encoding the third immunoglobulin repeat of DCC, resulting in frameshift and premature termination 36 amino acids downstream.

Show evidence (2 references)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Targeted sequencing of DCC in the proband of Family 2 revealed a homozygous 7 bp deletion in exon 4 (c.788_794delTTTCTGG) (Fig. 2e). Both parents were carriers."

Identifies the homozygous c.788_794delTTTCTGG variant in exon 4 of DCC.

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"It is at amino acid position 263 (of 1447) in the third immunoglobulin repeat, resulting in frameshift and premature termination 36 amino acids downstream (p.Val263Alafs*36)."

Details the protein consequence p.Val263Alafs*36 in the third immunoglobulin repeat.

NM_005215.3:c.2071C>A (p.Gln691Lys) Pathogenic

Gene: DCC hgnc:2701 missense variant

Homozygous missense variant in the third fibronectin type III repeat of DCC identified in an individual (Family 3, individual II:1) with complete agenesis of the corpus callosum, horizontal gaze palsy, progressive scoliosis, and preserved intellectual development.

Show evidence (2 references)

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"DCC sequencing in a cohort of 31 patients with ACC plus interhemispheric cyst did reveal one individual (Family 3, individual II:1; Supplementary Table 1, Fig. 2c, Supplementary note) with a homozygous missense variant (c.2071C>A, p.Gln691Lys) (Fig. 2f) affecting the third fibronectin repeat."

Identifies the homozygous missense variant c.2071C>A (p.Gln691Lys) affecting the third fibronectin repeat of DCC in Family 3.

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"One patient with a homozygous DCC c.2071C>A p.(Gln691Lys) did not have intellectual disability suggesting that pathogenic missense variants may result in a milder phenotype."

Notes that the homozygous p.Gln691Lys missense variant was associated with preserved intellectual function.

NM_005215.4:c.2399dupA (p.Asn800Lysfs*11) Pathogenic

Gene: DCC hgnc:2701 frameshift variant

Homozygous 1-bp duplication in exon 16 of DCC identified in three affected siblings from a consanguineous Pakistani family with HGPPS2 and intellectual disability.

Show evidence (1 reference)

PMID:33141514 SUPPORT PRIMARY RESULT Human Clinical

"A hypothesis-free, unbiased exome data analysis detected an insertion of nucleotide A (c.2399dupA) in exon 16 of the DCC gene. The insertion is predicted to cause frameshift p.(Asn800Lysfs*11)."

Documents the homozygous c.2399dupA (p.Asn800Lysfs*11) variant in exon 16 of DCC.

NM_005215.4:c.(?_1912)_(2359_?)dup (p.Ser788Tyrfs*4) Pathogenic

Gene: DCC hgnc:2701 tandem duplication

Homozygous intragenic tandem duplication encompassing exons 13-15 of DCC resulting in a predicted frameshift p.(Ser788Tyrfs*4).

Show evidence (1 reference)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"Exome sequencing revealed a homozygous apparently tandem duplication in the DCC (NM_005215.4):c.(?_1912)_(2359_?)dup, p.(Ser788Tyrfs*4); she has four copies of exons 13–15."

Identifies the homozygous intragenic tandem duplication of exons 13-15 in DCC.

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Medical Actions

3

Scoliosis Surgical Correction

Action: scoliosis surgical correction Ontology label: Spinal Fusion NCIT:C157986

Spinal instrumentation and surgical fusion for severe progressive thoracic and thoracolumbar scoliosis in childhood or adolescence to correct spinal deformity and preserve truncal balance and pulmonary function.

Target Phenotypes: Scoliosis HP:0002650

Show evidence (1 reference)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"She had a medical history of progressive scoliosis; at the age of 9 years, she had a thoracal scoliosis with a Cobb angle of 62° and a thoracolumbar scoliosis with a Cobb angle of 67°, which was operated. A month after the operation, she had a residual thoracal scoliosis with a Cobb angle of 15°..."

Documents substantial Cobb angle reduction following surgical correction of severe thoracic and thoracolumbar scoliosis in an HGPPS2 patient.

Physical Therapy and Neurodevelopmental Rehabilitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Supportive physical rehabilitation and developmental therapy are used in clinical management to address gross motor delay, gait instability, and axial musculoskeletal deformity, although formal clinical outcome data on rehabilitation efficacy in HGPPS remain limited.

Target Phenotypes: Global developmental delay HP:0001263 Scoliosis HP:0002650

Show evidence (1 reference)

PMID:38516134 NO_EVIDENCE PRIMARY RESULT Human Clinical

"Further evaluation of the natural neurodevelopmental trajectories of HGPPS patients with pathogenic variants and their benefits from physical rehabilitation is needed in the future for precise genetic counseling and clinical management."

Notes that while physical rehabilitation is considered in the clinical management of HGPPS spectrum disorders, systematic evaluation of its clinical benefit is still needed.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Genetic counseling for affected families regarding the 25% autosomal recessive recurrence risk, potential mild/incomplete penetrance phenotypes (isolated mirror movements or callosal agenesis) in heterozygous carriers, and options for prenatal or preimplantation genetic testing.

Show evidence (1 reference)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"Securing a diagnosis provides crucial information to the family for recurrence risk and allows the possibility to offer prenatal and preimplantation genetic diagnosis."

Highlights the importance of genetic counseling for recurrence risk assessment and reproductive options in families with HGPPS2.

🔬

Diagnosis

2

Brain Magnetic Resonance Imaging (MRI) and Diffusion Tractography

Structural brain MRI and diffusion tensor tractography demonstrate the pathognomonic combination of complete agenesis of the corpus callosum, absence of the anterior and hippocampal commissures, widely spaced lateral ventricles (racing car sign), longitudinal Probst bundles, and a deep midline cleft throughout the brainstem with a split pons, butterfly-shaped medulla oblongata, and absence of the superior cerebellar peduncle decussation (loss of the midbrain red dot sign on color fractional anisotropy maps).

magnetic resonance imaging of brain NCIT:C16809

Results: Agenesis of the corpus callosum, anterior commissure, and hippocampal commissure together with a split pons and butterfly-shaped medulla oblongata distinguishes HGPPS2 from ROBO3-related HGPPS1 (which has intact forebrain commissures).

Show evidence (2 references)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"In posterior fossa, pons was split in midline, and medulla oblongata showed a butterfly shape because of large midline cleft throughout the brainstem (Fig. 3). In supratentorial space, total agenesis of corpus callosum and other commissural tracts was evident. Widely spaced lateral ventricles,..."

Describes the diagnostic supratentorial and infratentorial brain MRI hallmarks of HGPPS2.

PMID:28250456 SUPPORT PRIMARY RESULT Human Clinical

"Color FA maps from our DCC(−/−) patient showed a similar failure of SCPs to decussate, as evidenced by absence of the typical midbrain “red dot” sign16 (Fig. 3c). In the pons, our patient had small middle cerebellar peduncles and also lacked evidence of transverse pontine fibers (Fig. 3c), like..."

Demonstrates diagnostic utility of diffusion tensor color fractional anisotropy maps showing absence of the midbrain decussation sign and transverse pontine fibers.

Molecular Genetic Testing of DCC (Sequencing and Copy-Number Analysis)

Exome or genome sequencing combined with copy-number variant (del/dup) analysis of DCC identifies biallelic pathogenic sequence variants or intragenic exon-level duplications and deletions.

molecular genetic testing NCIT:C15709

Results: Detection of homozygous or compound heterozygous pathogenic variants (including intragenic CNVs) in DCC confirms the diagnosis of HGPPS2 and enables carrier testing and prenatal diagnosis.

Show evidence (1 reference)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"The analysis of duplications and deletions in the DCC should be included in the routine genetic diagnostic evaluation of patients with suspected HGPPS2."

Recommends routine inclusion of DCC deletion/duplication analysis alongside sequence analysis in diagnostic evaluation.

📈

Progression

1

Onset

Age: Congenital / Neonatal

Commissural tract malformation and horizontal gaze palsy are congenital; progressive scoliosis develops and worsens during childhood and adolescence.

Show evidence (1 reference)

PMID:33141514 SUPPORT BACKGROUND Human Clinical

"Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development (HGPPS2) is a rare congenital disorder characterized by absence of conjugate horizontal eye movements, and progressive scoliosis developing in childhood and adolescence."

Confirms congenital disorder onset with childhood/adolescent progression of scoliosis.

📊

Prevalence

1

Global reported cases

Cases In Literature Ultra Rare

Ultra-rare congenital syndrome with 8 affected individuals from 5 families reported in the medical literature as of 2024.

Show evidence (1 reference)

PMID:38585553 SUPPORT PRIMARY RESULT Human Clinical

"To date, including the case reported here, three different homozygous pathogenic frameshift variants, one homozygous missense variant, and an intragenic duplication in the DCC gene have been reported in 8 patients with the HGPPS2 syndrome."

Documents the total number of reported HGPPS2 patients worldwide as 8 individuals.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Gaze_Palsy_Familial_Horizontal_With_Progressive_Scoliosis_2:

Horizontal gaze palsy with progressive scoliosis 1 (ROBO3-related HGPPS1) Not Yet Curated MONDO:0020790

Overlapping Features Autosomal recessive disorder caused by biallelic pathogenic variants in ROBO3 (OMIM 607313) that shares congenital horizontal gaze palsy, progressive childhood scoliosis, and a split pons with butterfly-shaped medulla oblongata. Unlike DCC-related HGPPS2, patients with ROBO3-related HGPPS1 have normal intelligence and intact forebrain commissures (normal corpus callosum, anterior commissure, and hippocampal commissure).

Distinguishing Features

Intact corpus callosum, anterior commissure, and hippocampal commissures on brain MRI
Normal intellectual development without global neurodevelopmental delay
Biallelic pathogenic variants in ROBO3 rather than DCC

Show evidence (3 references)

PMID:38516134 SUPPORT BACKGROUND Human Clinical

"HGPPS2 (OMIM1#617542) is caused by mutations of the DCC gene and distinguished from HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures."

Directly contrasts DCC-related HGPPS2 and ROBO3-related HGPPS1 by forebrain commissural agenesis and intellectual disability.

PMID:29068161 SUPPORT REVIEW SYNTHESIS Other

"Differential genetic diagnoses for DCC-MMs include NTN1 and RAD51 (MIM# 179617) [Depienne, et al., 2012; Méneret, et al., 2014a; Méneret, et al., 2017); for DCC-iACC include CDK5RAP2 (MIM# 608201, although only one family has been described to date [Jouan, et al., 2016)); and for DSBS include..."

Identifies ROBO3-related HGPPS1 as the primary differential diagnosis for developmental split-brain syndrome (HGPPS2).

PMID:15105459 SUPPORT PRIMARY RESULT Human Clinical

"In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain..."

Establishes ROBO3 mutations as the cause of hindbrain-restricted crossing defects in HGPPS1.

Mirror Movements 1 and/or Agenesis of the Corpus Callosum (Monoallelic DCC Spectrum) Not Yet Curated MONDO:0100515

Overlapping Features Autosomal dominant disorder with incomplete penetrance caused by heterozygous loss-of-function or missense variants in DCC, presenting with isolated congenital mirror movements of the upper limbs, isolated partial or complete agenesis of the corpus callosum, or both, without horizontal gaze palsy, brainstem clefting, or progressive scoliosis.

Distinguishing Features

Autosomal dominant (monoallelic) inheritance with incomplete penetrance
Absence of horizontal gaze palsy, progressive scoliosis, and midline brainstem cleft
Normal or near-normal neurodevelopment compared with biallelic HGPPS2

Show evidence (1 reference)

PMID:29068161 SUPPORT REVIEW SYNTHESIS Other

"Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS)."

Distinguishes the monoallelic DCC phenotype (mirror movements and/or isolated callosal agenesis) from biallelic developmental split-brain syndrome (HGPPS2).

{ }

Source YAML

click to show

name: Gaze_Palsy_Familial_Horizontal_With_Progressive_Scoliosis_2
creation_date: '2026-10-14T00:00:00Z'
category: Mendelian
parents:
- Horizontal gaze palsy with progressive scoliosis
- Rare genetic eye disease
- Neurodevelopmental disorder
disease_term:
  preferred_term: gaze palsy, familial horizontal, with progressive scoliosis, 2
  term:
    id: MONDO:0054602
    label: gaze palsy, familial horizontal, with progressive scoliosis, 2
synonyms:
- HGPPS2
- Horizontal gaze palsy with progressive scoliosis 2
- Horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development
- Developmental split-brain syndrome
- DSBS
description: >-
  Gaze palsy, familial horizontal, with progressive scoliosis, 2 (HGPPS2), also known
  as developmental split-brain syndrome (DSBS), is an ultra-rare autosomal recessive
  neurodevelopmental axon-guidance disorder caused by biallelic loss-of-function variants
  in the DCC gene encoding the netrin-1 receptor deleted in colorectal carcinoma. Unlike
  ROBO3-related HGPPS1, where midline crossing defects are restricted to the hindbrain and
  spinal cord, biallelic DCC deficiency disrupts commissural axon guidance across the entire
  central nervous system neuraxis. Hallmarks include congenital absence of conjugate horizontal
  eye movements, progressive childhood-onset neuromuscular scoliosis, global developmental
  delay, intellectual disability, complete agenesis of the corpus callosum with absence of
  anterior and hippocampal commissures, and a characteristic midline brainstem cleft with a
  split pons and butterfly-shaped medulla oblongata.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: COMPLETE
  description: >-
    Caused by homozygous or compound heterozygous loss-of-function variants in DCC;
    heterozygous carriers are either asymptomatic or may exhibit isolated congenital
    mirror movements or isolated agenesis of the corpus callosum with incomplete penetrance.
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Horizontal gaze palsy with progressive scoliosis-2 (HGPPS2, MIM 617542) with impaired intellectual development aka developmental split-brain syndrome is an ultra-rare congenital disorder caused by pathogenic biallelic variants in the deleted in colorectal cancer (DCC) gene."
    explanation: Confirms autosomal recessive inheritance via biallelic pathogenic DCC variants.
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "HGPPS2 phenotype caused by biallelic DCC variants appears to be fully penetrant and shows a similar clinical presentation including developmental delay, intellectual disability, neuromuscular scoliosis, horizontal gaze palsy, agenesis of corpus callosum, and the absence of cerebral commissures."
    explanation: Establishes complete penetrance of the full HGPPS2 syndrome in individuals with biallelic DCC loss-of-function variants.
  - reference: PMID:33141514
    reference_title: "A novel homozygous frameshift mutation in the DCC gene in a Pakistani family with autosomal recessive horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Sanger Sequencing confirmed the presence of the novel homozygous mutation in all three patients; the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern."
    explanation: Demonstrates autosomal recessive cosegregation in a multiplex consanguineous family.
prevalence:
- population: Global reported cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare congenital syndrome with 8 affected individuals from 5 families reported
    in the medical literature as of 2024.
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "To date, including the case reported here, three different homozygous pathogenic frameshift variants, one homozygous missense variant, and an intragenic duplication in the DCC gene have been reported in 8 patients with the HGPPS2 syndrome."
    explanation: Documents the total number of reported HGPPS2 patients worldwide as 8 individuals.
progression:
- phase: Onset
  age_range: Congenital / Neonatal
  notes: >-
    Commissural tract malformation and horizontal gaze palsy are congenital; progressive
    scoliosis develops and worsens during childhood and adolescence.
  evidence:
  - reference: PMID:33141514
    reference_title: "A novel homozygous frameshift mutation in the DCC gene in a Pakistani family with autosomal recessive horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development (HGPPS2) is a rare congenital disorder characterized by absence of conjugate horizontal eye movements, and progressive scoliosis developing in childhood and adolescence."
    explanation: Confirms congenital disorder onset with childhood/adolescent progression of scoliosis.
mechanistic_hypotheses:
- hypothesis_group_id: scoliosis_spinal_interneuron_hypothesis
  hypothesis_label: Defective Spinal Commissural Interneuron Circuitry and Paraspinal Muscle Imbalance Driving Progressive Scoliosis
  status: EMERGING
  description: >-
    Progressive childhood and adolescent scoliosis in HGPPS2 is hypothesized to result
    from defective midline crossing of spinal cord commissural interneurons (which coordinate
    left-right axial locomotor and postural motor networks in animal models of Netrin-1/DCC
    deficiency), leading to chronic paraspinal muscle activation imbalance during spinal growth.
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "We speculate that scoliosis may pertain to unbalanced paraspinal muscle activity due to defective spinal interneuron circuits (required for coordination of left-right locomotory patterns), since these circuits have been shown to be disrupted in Netrin-1 and DCC-deficient mice29,30."
    explanation: Explicitly frames the link between defective spinal interneuron circuits, unbalanced paraspinal muscle activity, and progressive scoliosis as a mechanistic hypothesis supported by mouse knockout studies.
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The pathogenesis of progressive scoliosis in the disorder might arise from defective spinal commissural interneurons or paraspinal muscle activation imbalance"
    explanation: Summarizes the proposed neurogenic mechanism linking spinal commissural interneuron defects and paraspinal muscle activation imbalance to progressive scoliosis.
pathophysiology:
- name: Loss of DCC Netrin-1 Receptor Function
  description: >-
    Biallelic exon-skipping deletion, frameshift, intragenic duplication, or loss-of-function
    missense variants in DCC abolish or severely impair the deleted in colorectal carcinoma
    (DCC) transmembrane receptor protein. DCC normally binds extracellular netrin-1 (NTN1)
    and forms a molecular complex with ROBO3 to silence Slit-mediated repulsion and transduce
    attractive and long-range guidance cues required for developing commissural axons to
    approach and cross the anatomical midline of the central nervous system.
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: DCC
    term:
      id: hgnc:2701
      label: DCC
  molecular_functions:
  - preferred_term: netrin receptor activity
    term:
      id: GO:0005042
      label: netrin receptor activity
  cell_types:
  - preferred_term: central nervous system neuron
    term:
      id: CL:0000117
      label: CNS neuron (sensu Vertebrata)
  biological_processes:
  - preferred_term: netrin-activated signaling pathway
    term:
      id: GO:0038007
      label: netrin-activated signaling pathway
  - preferred_term: commissural neuron axon guidance
    term:
      id: GO:0071679
      label: commissural neuron axon guidance
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported."
    explanation: Establishes biallelic loss-of-function variants in the axon-guidance receptor gene DCC as the primary molecular defect.
  - reference: PMID:29068161
    reference_title: "DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "DCC is required for the transduction of NTN1-induced attractive and long-range repulsive signaling in the coordinated outgrowth and guidance of commissural axons that cross the anatomical midline of the body"
    explanation: Details the role of DCC in transducing netrin-1 signaling to guide midline-crossing commissural axons.
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "Instead, Robo3 forms a direct molecular complex with DCC that silences repulsion from Slits33 (allowing developing neurons to approach) and enhances attraction to Netrins33,34."
    explanation: Explains how DCC and ROBO3 interact molecularly in animal models to coordinate midline axon attraction and repulsion silencing.
  downstream:
  - target: Pan-Neuraxis Commissural Axon Midline Crossing Failure
    description: >-
      Absence of DCC-mediated netrin-1 attraction prevents pioneering commissural axons
      from crossing the midline across the forebrain, midbrain, hindbrain, and spinal cord.
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS."
      explanation: Demonstrates that loss of DCC directly disrupts midline crossing across the entire human CNS.

- name: Pan-Neuraxis Commissural Axon Midline Crossing Failure
  description: >-
    Without functional DCC signaling, commissural axons fail to cross the anatomical midline
    at multiple levels of the central nervous system neuraxis, accompanied by broad
    disorganization of central nervous system white-matter architecture.
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: central nervous system neuron
    term:
      id: CL:0000117
      label: CNS neuron (sensu Vertebrata)
  biological_processes:
  - preferred_term: axon guidance
    term:
      id: GO:0007411
      label: axon guidance
  - preferred_term: central nervous system projection neuron axonogenesis
    term:
      id: GO:0021952
      label: central nervous system projection neuron axonogenesis
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis."
    explanation: Diffusion tractography and structural MRI confirm pan-neuraxis loss of commissural tracts.
  downstream:
  - target: Forebrain Commissural Tract Agenesis
    description: >-
      Failure of pioneering cingulate and neocortical commissural axons to cross the
      telencephalic midline prevents formation of the corpus callosum, anterior commissure,
      and hippocampal commissure.
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "The forebrain crossing deficits observed in our patients are reminiscent of abnormalities previously reported in mouse knockout models of Netrin-1 or DCC deficiency, which are also acallosal19–21. This is thought to be due to failure of DCC signaling in pioneering commissural axons from the cingulate and neocortex22,23."
      explanation: Connects DCC signaling failure in pioneering cortical axons to forebrain commissural agenesis based on conserved mouse and human phenotypes.
  - target: Non-Commissural Forebrain White-Matter Disorganization
    description: >-
      Pan-neuraxis DCC loss also disrupts organization of non-commissural forebrain
      white-matter projection tracts.
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Our patients’ cognitive deficits may at least partially be attributable to non-commissural forebrain white matter abnormalities as well."
      explanation: Documents non-commissural forebrain white-matter abnormalities alongside commissural agenesis.
  - target: Abducens-to-Oculomotor Internuclear Crossing Failure
    description: >-
      Failure of internuclear commissural axons linking the abducens nucleus and contralateral
      oculomotor nucleus to cross the brainstem midline.
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Individuals with DCC(−/−) mutations have brainstem flattening/midline clefting and eye movement abnormalities similar to those seen in HGPPS5,14, reflecting shared brainstem crossing defects disrupting pathways controlling conjugate gaze."
      explanation: Links brainstem midline crossing failure to disruption of pathways controlling conjugate horizontal gaze.
  - target: Midline Brainstem Clefting and Pontomedullary Hypoplasia
    description: >-
      Absence of crossing transverse pontine and medullary decussating fibers produces
      pontine and midbrain hypoplasia and a deep midline cleft across the brainstem.
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla (Supplementary Table 1, Supplementary Fig. 1b–g)."
      explanation: Demonstrates that midline crossing failure across the brainstem produces pontomedullary hypoplasia and a deep midline cleft.
  - target: Superior Cerebellar Peduncle Decussation Failure
    description: >-
      Failure of cerebellar efferent axons in the superior cerebellar peduncles to cross
      at the midbrain decussation (commissure of Wernekinck).
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Color FA maps from our DCC(−/−) patient showed a similar failure of SCPs to decussate, as evidenced by absence of the typical midbrain “red dot” sign16 (Fig. 3c). In the pons, our patient had small middle cerebellar peduncles and also lacked evidence of transverse pontine fibers (Fig. 3c), like patients with HGPPS."
      explanation: Diffusion tractography confirms failure of superior cerebellar peduncle decussation in the midbrain.
  - target: Corticospinal Tract Pyramidal Decussation Deficit
    description: >-
      Reduced midline crossing of descending corticospinal tract axons at the medullary
      pyramidal decussation.
    evidence:
    - reference: PMID:29068161
      reference_title: "DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Individuals with DSBS may also present with MMs, which are associated with the reduced midline crossing of descending CST projections at the pyramidal decussation"
      explanation: Connects pan-neuraxis midline crossing failure to reduced corticospinal tract decussation at the medullary pyramids.
  - target: Defective Spinal Commissural Interneuron Circuitry
    description: >-
      Midline crossing failure extends to spinal cord commissural interneurons required
      for bilateral axial motor coordination.
    hypothesis_groups:
    - scoliosis_spinal_interneuron_hypothesis
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "We speculate that scoliosis may pertain to unbalanced paraspinal muscle activity due to defective spinal interneuron circuits (required for coordination of left-right locomotory patterns), since these circuits have been shown to be disrupted in Netrin-1 and DCC-deficient mice29,30."
      explanation: Links DCC deficiency to defective spinal commissural interneuron circuits based on mouse knockout models.

- name: Forebrain Commissural Tract Agenesis
  description: >-
    Complete developmental absence of the major telencephalic and diencephalic commissures,
    including the corpus callosum, anterior commissure, and hippocampal commissure,
    eliminating direct interhemispheric commissural connectivity.
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: corpus callosum development
    term:
      id: GO:0022038
      label: corpus callosum development
  - preferred_term: forebrain morphogenesis
    term:
      id: GO:0048853
      label: forebrain morphogenesis
  locations:
  - preferred_term: corpus callosum
    term:
      id: UBERON:0002336
      label: corpus callosum
  - preferred_term: anterior commissure
    term:
      id: UBERON:0000935
      label: anterior commissure
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "MR brain imaging revealed a number of abnormalities in the affected individuals (Supplementary Table 1, Fig. 1, Supplementary Fig. 1), including ACC and absence of the anterior (AC) and hippocampal commissures (HC)."
    explanation: Confirms complete absence of the corpus callosum, anterior commissure, and hippocampal commissure on brain MRI.
  downstream:
  - target: Longitudinal Probst Bundle Misrouting
    description: >-
      Callosal axons that fail to cross the interhemispheric fissure are diverted
      ipsilaterally into longitudinal Probst bundles along the lateral ventricles.
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "DCC(−/−) reconstructions did reveal characteristic, longitudinally misguided Probst bundles along the lateral ventricles (Supplementary Fig. 7b), a classic finding in some individuals with agenesis of the corpus callosum14."
      explanation: Demonstrates that uncrossed callosal fibers form longitudinal Probst bundles along the lateral ventricles.
  - target: Agenesis of corpus callosum
    description: >-
      Failure of callosal commissural axons to cross the telencephalic midline directly
      manifests clinically and radiologically as complete agenesis of the corpus callosum.
    evidence:
    - reference: PMID:38585553
      reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "In supratentorial space, total agenesis of corpus callosum and other commissural tracts was evident. Widely spaced lateral ventricles, often called as racing car sign, could be seen."
      explanation: Directly links forebrain commissural tract agenesis to the radiological phenotype of corpus callosum agenesis.

- name: Longitudinal Probst Bundle Misrouting
  description: >-
    Uncrossed callosal axons accumulate ipsilaterally as longitudinally oriented Probst
    bundles running parallel to widely spaced lateral ventricles, producing the radiological
    racing car sign.
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: corpus callosum development
    term:
      id: GO:0022038
      label: corpus callosum development
  locations:
  - preferred_term: corpus callosum
    term:
      id: UBERON:0002336
      label: corpus callosum
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "DCC(−/−) reconstructions did reveal characteristic, longitudinally misguided Probst bundles along the lateral ventricles (Supplementary Fig. 7b), a classic finding in some individuals with agenesis of the corpus callosum14."
    explanation: Documents longitudinal Probst bundle formation along the lateral ventricles on diffusion tractography.

- name: Non-Commissural Forebrain White-Matter Disorganization
  description: >-
    Disorganization of non-commissural intrahemispheric and projection white-matter tracts
    in the forebrain accompanies complete commissural agenesis and impairs cognitive,
    behavioral, and neurodevelopmental maturation.
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: forebrain morphogenesis
    term:
      id: GO:0048853
      label: forebrain morphogenesis
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Our patients’ cognitive deficits may at least partially be attributable to non-commissural forebrain white matter abnormalities as well."
    explanation: Connects non-commissural forebrain white-matter tract abnormalities to cognitive and neurodevelopmental impairment in HGPPS2.
  downstream:
  - target: Intellectual disability
    description: >-
      Combined forebrain commissural agenesis and non-commissural forebrain white-matter
      disorganization impair cognitive development.
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Our patients’ cognitive deficits may at least partially be attributable to non-commissural forebrain white matter abnormalities as well."
      explanation: Attributes cognitive impairment in HGPPS2 to forebrain white-matter abnormalities.
  - target: Global developmental delay
    description: >-
      Supratentorial and pan-neuraxis white-matter tract disorganization delays early motor
      and speech milestone acquisition.
    evidence:
    - reference: PMID:38516134
      reference_title: "Novel variants and phenotypes of ROBO3 gene associated with horizontal gaze palsy with progressive scoliosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "HGPPS2 (OMIM1#617542) is caused by mutations of the DCC gene and distinguished from HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures."
      explanation: Links the forebrain commissural and white-matter involvement specific to DCC-related HGPPS2 with global developmental delay.

- name: Abducens-to-Oculomotor Internuclear Crossing Failure
  description: >-
    Loss of the internuclear commissural tract connecting the abducens nucleus (CN VI) across
    the brainstem midline to the contralateral medial oculomotor nucleus (CN III) via the
    medial longitudinal fasciculus abolishes conjugate horizontal eye movements while
    sparing vertical gaze.
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: hindbrain development
    term:
      id: GO:0030902
      label: hindbrain development
  locations:
  - preferred_term: brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  - preferred_term: pons
    term:
      id: UBERON:0000988
      label: pons
  - preferred_term: medial oculomotor nucleus
    term:
      id: UBERON:0002975
      label: medial oculomotor nucleus
  evidence:
  - reference: PMID:29068161
    reference_title: "DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "These appear to include the decussation of the superior cerebellar peduncles (also referred to as the commissure of Wernekinck) that connects the cerebellum to the midbrain, and the commissural tract linking the lateral abducens and medial occulomotor nerves, required for conjugate horizontal eye movement"
    explanation: Identifies the specific internuclear abducens-to-oculomotor commissural tract disruption underlying conjugate horizontal gaze palsy.
  downstream:
  - target: Horizontal gaze palsy
    description: >-
      Absence of the crossed abducens-to-oculomotor internuclear pathway prevents coordinated
      abduction of one eye with adduction of the contralateral eye, causing congenital
      horizontal gaze palsy.
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Individuals with DCC(−/−) mutations have brainstem flattening/midline clefting and eye movement abnormalities similar to those seen in HGPPS5,14, reflecting shared brainstem crossing defects disrupting pathways controlling conjugate gaze."
      explanation: Directly connects brainstem internuclear crossing failure to congenital conjugate horizontal gaze palsy.

- name: Midline Brainstem Clefting and Pontomedullary Hypoplasia
  description: >-
    Absence of transverse pontine fibers and decussating medullary tracts produces hypoplastic
    pons and midbrain structures, small middle cerebellar peduncles, and a deep midline cleft
    extending through the pons (split pons sign) and medulla oblongata (butterfly medulla).
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: hindbrain development
    term:
      id: GO:0030902
      label: hindbrain development
  locations:
  - preferred_term: brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  - preferred_term: pons
    term:
      id: UBERON:0000988
      label: pons
  - preferred_term: medulla oblongata
    term:
      id: UBERON:0001896
      label: medulla oblongata
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla (Supplementary Table 1, Supplementary Fig. 1b–g)."
    explanation: Describes the characteristic brainstem hypoplasia, midline cleft, and butterfly-shaped medulla.
  downstream:
  - target: Midline brainstem cleft
    description: >-
      Failure of pontine and medullary midline crossing fibers creates a deep dorsal and
      ventral midline cleft splitting the pons and shaping the medulla like a butterfly.
    evidence:
    - reference: PMID:38585553
      reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "In posterior fossa, pons was split in midline, and medulla oblongata showed a butterfly shape because of large midline cleft throughout the brainstem (Fig. 3)."
      explanation: Directly links midline brainstem clefting to the split pons and butterfly medulla neuroimaging phenotype.
  - target: Hypoplasia of the brainstem
    description: >-
      Depletion of transverse pontine and decussating brainstem fiber bundles reduces the
      volume of the pons, midbrain, and middle cerebellar peduncles.
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla (Supplementary Table 1, Supplementary Fig. 1b–g)."
      explanation: Documents hypoplasia of the pons and midbrain structures on neuroimaging.

- name: Superior Cerebellar Peduncle Decussation Failure
  description: >-
    Absence of crossing fibers in the decussation of the superior cerebellar peduncles
    (commissure of Wernekinck), demonstrated by absence of the normal midbrain red dot sign
    on directional diffusion tensor color fractional anisotropy maps, impairs cerebellar
    efferent coordination.
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: hindbrain development
    term:
      id: GO:0030902
      label: hindbrain development
  locations:
  - preferred_term: brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Color FA maps from our DCC(−/−) patient showed a similar failure of SCPs to decussate, as evidenced by absence of the typical midbrain “red dot” sign16 (Fig. 3c). In the pons, our patient had small middle cerebellar peduncles and also lacked evidence of transverse pontine fibers (Fig. 3c), like patients with HGPPS."
    explanation: Tractography shows absence of superior cerebellar peduncle decussation and small middle cerebellar peduncles.
  downstream:
  - target: Ataxia
    description: >-
      Disrupted cerebellar-midbrain efferent decussation and hypoplastic cerebellar peduncles
      impair cerebellar coordination of gait, manifesting as broad-based ataxia.
    evidence:
    - reference: PMID:38585553
      reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "She had poor eye contact and stereotypic repetitive wringing hand movements, but no mirror movements were noted. Her gait was broad based and ataxic."
      explanation: Documents broad-based ataxic gait in an affected HGPPS2 patient with hindbrain/cerebellar tract involvement.

- name: Corticospinal Tract Pyramidal Decussation Deficit
  description: >-
    Reduced midline crossing of descending corticospinal tract projections at the pyramidal
    decussation in the lower medulla results in aberrant ipsilateral or bilateral motor
    cortex projection to spinal motor neurons in a subset of patients.
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: hindbrain development
    term:
      id: GO:0030902
      label: hindbrain development
  locations:
  - preferred_term: medulla oblongata
    term:
      id: UBERON:0001896
      label: medulla oblongata
  evidence:
  - reference: PMID:29068161
    reference_title: "DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Individuals with DSBS may also present with MMs, which are associated with the reduced midline crossing of descending CST projections at the pyramidal decussation"
    explanation: Explains how reduced corticospinal tract decussation in the lower medulla leads to mirror movements.
  downstream:
  - target: Mirror movements
    description: >-
      Unilateral voluntary motor commands transmitted via uncrossed corticospinal fibers
      produce involuntary synchronous contralateral mirror movements of the hands.
    evidence:
    - reference: PMID:29068161
      reference_title: "DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Individuals with DSBS may also present with MMs, which are associated with the reduced midline crossing of descending CST projections at the pyramidal decussation [Jamuar, et al., 2017]."
      explanation: Directly links reduced corticospinal tract pyramidal decussation to congenital mirror movements in HGPPS2/DSBS.

- name: Defective Spinal Commissural Interneuron Circuitry
  description: >-
    Defective midline crossing of spinal cord commissural interneurons disrupts local spinal
    central pattern generator networks that coordinate left-right axial motor and
    proprioceptive signaling.
  mechanism_confidence: HYPOTHETICAL
  locations:
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "We speculate that scoliosis may pertain to unbalanced paraspinal muscle activity due to defective spinal interneuron circuits (required for coordination of left-right locomotory patterns), since these circuits have been shown to be disrupted in Netrin-1 and DCC-deficient mice29,30."
    explanation: Proposes defective spinal commissural interneuron circuitry (demonstrated in Netrin-1 and DCC-deficient mice) as the upstream spinal mechanism in HGPPS2.
  downstream:
  - target: Paraspinal Muscle Activation Imbalance
    description: >-
      Impaired bilateral coordination across spinal commissural interneuron circuits is
      hypothesized to cause asymmetric paraspinal muscle tone and activation.
    hypothesis_groups:
    - scoliosis_spinal_interneuron_hypothesis
    evidence:
    - reference: PMID:38585553
      reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "The pathogenesis of progressive scoliosis in the disorder might arise from defective spinal commissural interneurons or paraspinal muscle activation imbalance"
      explanation: Links defective spinal commissural interneurons to paraspinal muscle activation imbalance in the hypothesized pathogenesis of scoliosis.

- name: Paraspinal Muscle Activation Imbalance
  description: >-
    Chronic asymmetrical activation of paraspinal musculature during childhood and adolescent
    axial skeletal growth drives progressive lateral curvature of the thoracic and
    thoracolumbar spine.
  mechanism_confidence: HYPOTHETICAL
  locations:
  - preferred_term: vertebral column
    term:
      id: UBERON:0001130
      label: vertebral column
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The pathogenesis of progressive scoliosis in the disorder might arise from defective spinal commissural interneurons or paraspinal muscle activation imbalance"
    explanation: Summarizes the hypothesized role of paraspinal muscle activation imbalance in driving progressive scoliosis.
  downstream:
  - target: Scoliosis
    description: >-
      Unbalanced paraspinal muscle forces across the growing vertebral column produce
      progressive childhood and adolescent thoracic and thoracolumbar scoliosis.
    hypothesis_groups:
    - scoliosis_spinal_interneuron_hypothesis
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "We speculate that scoliosis may pertain to unbalanced paraspinal muscle activity due to defective spinal interneuron circuits (required for coordination of left-right locomotory patterns), since these circuits have been shown to be disrupted in Netrin-1 and DCC-deficient mice29,30."
      explanation: Connects unbalanced paraspinal muscle activity to the clinical development of progressive scoliosis.
phenotypes:
- category: Ophthalmologic
  name: Horizontal gaze palsy
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Congenital complete absence of conjugate horizontal eye movements (saccades, smooth
    pursuit, and horizontal optokinetic nystagmus) with preserved vertical conjugate gaze
    and pupillary reflexes, present in 8/8 (100%) reported patients.
  notes: >-
    Bound to HP:0000549 (Abnormal conjugate eye movement) rather than HP:0025590 (Horizontal
    supranuclear gaze palsy) because HPO restricts its horizontal gaze palsy term to
    supranuclear lesions, whereas horizontal gaze palsy in HGPPS2 results from internuclear
    brainstem midline crossing failure between the abducens and oculomotor nuclei.
  phenotype_term:
    preferred_term: Horizontal gaze palsy
    term:
      id: HP:0000549
      label: Abnormal conjugate eye movement
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in the brainstem, agenesis of corpus callosum, and absence of cerebral commissures present in all patients whose brain MRI result was available (N = 7/7, 100%). Common presenting features were global developmental delay, intellectual disability (N = 5/8, 63%), scoliosis (N = 7/8, 88%), short stature (N = 3/5, 60%), and behavioral problems (N = 3/5, 60%)."
    explanation: Establishes horizontal gaze palsy as an obligate hallmark present in 8/8 (100%) patients.
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Her vertical eye movements were full and conjugated, but she lacked all horizontal eye movements, even horizontal optokinetic nystagmus. Her direct and consensual pupillary reflexes were normal. Cycloplegic refraction showed mild hyperopia."
    explanation: Illustrates complete absence of horizontal eye movements with preserved vertical conjugate gaze.

- category: Neurological
  name: Agenesis of corpus callosum
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Complete absence of the corpus callosum accompanied by absence of the anterior and
    hippocampal commissures, longitudinal Probst bundles, and widely spaced lateral
    ventricles (racing car sign), present in 7/7 (100%) patients evaluated by brain MRI.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in the brainstem, agenesis of corpus callosum, and absence of cerebral commissures present in all patients whose brain MRI result was available (N = 7/7, 100%). Common presenting features were global developmental delay, intellectual disability (N = 5/8, 63%), scoliosis (N = 7/8, 88%), short stature (N = 3/5, 60%), and behavioral problems (N = 3/5, 60%)."
    explanation: Confirms agenesis of the corpus callosum and absence of cerebral commissures in 7/7 (100%) imaged patients.
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In posterior fossa, pons was split in midline, and medulla oblongata showed a butterfly shape because of large midline cleft throughout the brainstem (Fig. 3). In supratentorial space, total agenesis of corpus callosum and other commissural tracts was evident. Widely spaced lateral ventricles, often called as racing car sign, could be seen."
    explanation: Details the characteristic supratentorial MRI appearance of total callosal agenesis and widely spaced lateral ventricles.

- category: Neurological
  name: Midline brainstem cleft
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Deep sagittal midline cleft extending throughout the pons (split pons sign) and medulla
    oblongata (butterfly-shaped medulla), present in 7/7 (100%) patients evaluated by brain MRI.
  phenotype_term:
    preferred_term: Midline brainstem cleft
    term:
      id: HP:0033645
      label: Midline brainstem cleft
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla (Supplementary Table 1, Supplementary Fig. 1b–g)."
    explanation: Documents the pathognomonic midline cleft throughout the brainstem and butterfly-shaped medulla.
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in the brainstem, agenesis of corpus callosum, and absence of cerebral commissures present in all patients whose brain MRI result was available (N = 7/7, 100%). Common presenting features were global developmental delay, intellectual disability (N = 5/8, 63%), scoliosis (N = 7/8, 88%), short stature (N = 3/5, 60%), and behavioral problems (N = 3/5, 60%)."
    explanation: Confirms midline brainstem cleft in 7/7 (100%) patients who underwent neuroimaging.

- category: Neurological
  name: Hypoplasia of the brainstem
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Hypoplasia of the pons, midbrain, and middle cerebellar peduncles accompanying absence
    of transverse pontine fibers and superior cerebellar peduncle decussation on brain MRI.
  phenotype_term:
    preferred_term: Hypoplasia of the brainstem
    term:
      id: HP:0002365
      label: Hypoplasia of the brainstem
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla (Supplementary Table 1, Supplementary Fig. 1b–g)."
    explanation: Confirms hypoplasia of the pons and midbrain structures across imaged patients.
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Color FA maps from our DCC(−/−) patient showed a similar failure of SCPs to decussate, as evidenced by absence of the typical midbrain “red dot” sign16 (Fig. 3c). In the pons, our patient had small middle cerebellar peduncles and also lacked evidence of transverse pontine fibers (Fig. 3c), like patients with HGPPS."
    explanation: Documents small middle cerebellar peduncles and absence of transverse pontine fibers contributing to pontine hypoplasia.

- category: Musculoskeletal
  name: Scoliosis
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Progressive childhood- and adolescent-onset thoracic or thoracolumbar neuromuscular
    scoliosis (7/8 reported patients, 88%), frequently severe enough to require surgical
    spinal fusion.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in the brainstem, agenesis of corpus callosum, and absence of cerebral commissures present in all patients whose brain MRI result was available (N = 7/7, 100%). Common presenting features were global developmental delay, intellectual disability (N = 5/8, 63%), scoliosis (N = 7/8, 88%), short stature (N = 3/5, 60%), and behavioral problems (N = 3/5, 60%)."
    explanation: Establishes scoliosis in 7/8 (88%) reported patients.
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "She had a medical history of progressive scoliosis; at the age of 9 years, she had a thoracal scoliosis with a Cobb angle of 62° and a thoracolumbar scoliosis with a Cobb angle of 67°, which was operated. A month after the operation, she had a residual thoracal scoliosis with a Cobb angle of 15° and a thoracolumbar scoliosis with a Cobb angle of 13° (Fig. 1)."
    explanation: Documents severe progressive thoracic and thoracolumbar scoliosis requiring surgical correction.

- category: Neurodevelopmental
  name: Global developmental delay
  frequency: FREQUENT
  description: >-
    Marked delay in motor and speech milestones from infancy, such as delayed rolling,
    crawling, and independent ambulation.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "She has had significant failure to thrive, and her development has been remarkably delayed. She learned to roll from belly to back at the age of 2 years, crawl at the age of 5 years, and walk with mild support at the age of 8 years"
    explanation: Illustrates profound motor milestone delay in an affected patient.
  - reference: PMID:38516134
    reference_title: "Novel variants and phenotypes of ROBO3 gene associated with horizontal gaze palsy with progressive scoliosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "HGPPS2 (OMIM1#617542) is caused by mutations of the DCC gene and distinguished from HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures."
    explanation: Highlights global developmental delay as a key clinical feature distinguishing HGPPS2 from HGPPS1.

- category: Neurodevelopmental
  name: Intellectual disability
  frequency: FREQUENT
  description: >-
    Impaired intellectual development ranging from mild to severe, documented in 5/8 (63%)
    reported patients; the three without intellectual disability are the p.Gln691Lys
    missense patient (PMID:28250456) and two of the three Pakistani siblings (PMID:33141514).
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in the brainstem, agenesis of corpus callosum, and absence of cerebral commissures present in all patients whose brain MRI result was available (N = 7/7, 100%). Common presenting features were global developmental delay, intellectual disability (N = 5/8, 63%), scoliosis (N = 7/8, 88%), short stature (N = 3/5, 60%), and behavioral problems (N = 3/5, 60%)."
    explanation: Documents intellectual disability in 5/8 (63%) reported patients.

- category: Growth
  name: Short stature
  frequency: FREQUENT
  description: >-
    Postnatal growth retardation and short stature accompanied by early failure to thrive,
    reported in 3/5 (60%) evaluated patients.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in the brainstem, agenesis of corpus callosum, and absence of cerebral commissures present in all patients whose brain MRI result was available (N = 7/7, 100%). Common presenting features were global developmental delay, intellectual disability (N = 5/8, 63%), scoliosis (N = 7/8, 88%), short stature (N = 3/5, 60%), and behavioral problems (N = 3/5, 60%)."
    explanation: Reports short stature in 3/5 (60%) evaluated patients.

- category: Psychiatric / Behavioral
  name: Atypical behavior
  frequency: FREQUENT
  description: >-
    Behavioral abnormalities including poor eye contact, stereotypic repetitive hand-wringing
    movements, and self-injurious or autistic-like behaviors, reported in 3/5 (60%) evaluated
    patients.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in the brainstem, agenesis of corpus callosum, and absence of cerebral commissures present in all patients whose brain MRI result was available (N = 7/7, 100%). Common presenting features were global developmental delay, intellectual disability (N = 5/8, 63%), scoliosis (N = 7/8, 88%), short stature (N = 3/5, 60%), and behavioral problems (N = 3/5, 60%)."
    explanation: Reports behavioral problems in 3/5 (60%) evaluated patients.
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "She had poor eye contact and stereotypic repetitive wringing hand movements, but no mirror movements were noted. Her gait was broad based and ataxic."
    explanation: Describes stereotypic repetitive hand-wringing and poor eye contact in an affected patient.

- category: Neurological
  name: Mirror movements
  frequency: OCCASIONAL
  description: >-
    Involuntary contralateral mirror movements of the hands and upper limbs due to reduced
    corticospinal tract decussation at the medullary pyramids, observed in a minority of
    affected individuals (such as the proband of Family 1 in Jamuar et al., but absent in
    Families 2 and 3 and in the 2024 duplication case).
  phenotype_term:
    preferred_term: Mirror movements
    term:
      id: HP:0001335
      label: Bimanual synkinesia
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Furthermore, while the proband in Family 1 exhibited mirror movements, the affected individuals in Family 2 and 3 did not."
    explanation: Provides primary clinical evidence that mirror movements occur in a minority (1 of 3 families in the original cohort) of biallelic DCC cases.
  - reference: PMID:29068161
    reference_title: "DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Individuals with DSBS may also present with MMs, which are associated with the reduced midline crossing of descending CST projections at the pyramidal decussation [Jamuar, et al., 2017]."
    explanation: Confirms that patients with developmental split-brain syndrome (HGPPS2) may occasionally present with congenital mirror movements.

- category: Neurological
  name: Ataxia
  frequency: OCCASIONAL
  description: >-
    Broad-based ataxic gait reflecting impaired cerebellar-midbrain connectivity and absence
    of superior cerebellar peduncle decussation.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "She had poor eye contact and stereotypic repetitive wringing hand movements, but no mirror movements were noted. Her gait was broad based and ataxic."
    explanation: Documents a broad-based ataxic gait on neurological examination.
genetic:
- name: DCC
  association: Causal Biallelic Loss-of-Function Variants
  gene_term:
    preferred_term: DCC
    term:
      id: hgnc:2701
      label: DCC
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Homozygous loss-of-function variants in DCC (18q21.2), including a 7682 bp deletion
    removing the 3' end of exon 1 and causing complete exon 1 skipping (chr18:49867185-49874867del,
    predicted p.Pro11Thrfs*15), frameshift deletions and duplications (c.788_794delTTTCTGG /
    p.Val263Alafs*36 and c.2399dupA / p.Asn800Lysfs*11), a multi-exon tandem duplication of
    exons 13-15 (c.(?_1912)_(2359_?)dup / p.Ser788Tyrfs*4), and a homozygous missense variant
    in the third fibronectin type III repeat (c.2071C>A / p.Gln691Lys), cause loss of
    netrin-1 receptor signaling and pan-neuraxis commissural agenesis.
  evidence:
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported."
    explanation: Identifies biallelic loss-of-function mutations in DCC as the genetic cause of developmental split-brain syndrome / HGPPS2.
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "To date, including the case reported here, three different homozygous pathogenic frameshift variants, one homozygous missense variant, and an intragenic duplication in the DCC gene have been reported in 8 patients with the HGPPS2 syndrome."
    explanation: Summarizes the allelic spectrum of pathogenic biallelic DCC variants across all 8 reported HGPPS2 patients.
  variants:
  - name: Homozygous 7682 bp exon 1 deletion (NM_005215.3 exon 1 skipping / p.Pro11Thrfs*15)
    description: >-
      Homozygous 7682 bp deletion (chr18:49867185-49874867del) removing 61 bp at the 3' end
      of coding exon 1 and 7.6 kb of intron 1 in DCC, causing complete skipping of exon 1
      (which encodes the signal peptide and first immunoglobulin repeat) and acting as a
      functional null allele in two siblings from Family 1.
    gene:
      preferred_term: DCC
      term:
        id: hgnc:2701
        label: DCC
    type: deletion
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "A series of PCR probes (Supplementary Fig. 4b) was used to localize the precise breakpoint (Supplementary Fig. 4c), revealing a 7682 bp deletion (Fig. 2d). This deletion removed the 3′ end of exon 1, containing 61 bp of DCC coding sequence (NM_005215.3) and 7.6 kb of intronic sequence (Fig. 2d). RT-PCR from patient lymphoblasts demonstrated that this deletion causes exon 1 to be skipped entirely (Supplementary Fig. 5a–c)."
      explanation: Characterizes the homozygous 7682 bp deletion removing the 3' end of exon 1 and demonstrates complete exon 1 skipping in patient lymphoblasts.
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Exon 1 is the first coding exon and contains the signal peptide, required for correct orientational insertion into the membrane, and part of the first of DCC’s four immunoglobulin repeats, which adopt a horseshoe configuration critical for netrin-mediated guidance12. Disruption of these features strongly predicts that this mutation represents a functional null."
      explanation: Demonstrates that loss of exon 1 disrupts the signal peptide and first immunoglobulin domain, producing a functional null allele.
  - name: NM_005215.3:c.788_794delTTTCTGG (p.Val263Alafs*36)
    description: >-
      Homozygous 7-bp deletion in exon 4 encoding the third immunoglobulin repeat of DCC,
      resulting in frameshift and premature termination 36 amino acids downstream.
    gene:
      preferred_term: DCC
      term:
        id: hgnc:2701
        label: DCC
    type: frameshift_variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Targeted sequencing of DCC in the proband of Family 2 revealed a homozygous 7 bp deletion in exon 4 (c.788_794delTTTCTGG) (Fig. 2e). Both parents were carriers."
      explanation: Identifies the homozygous c.788_794delTTTCTGG variant in exon 4 of DCC.
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "It is at amino acid position 263 (of 1447) in the third immunoglobulin repeat, resulting in frameshift and premature termination 36 amino acids downstream (p.Val263Alafs*36)."
      explanation: Details the protein consequence p.Val263Alafs*36 in the third immunoglobulin repeat.
  - name: NM_005215.3:c.2071C>A (p.Gln691Lys)
    description: >-
      Homozygous missense variant in the third fibronectin type III repeat of DCC identified
      in an individual (Family 3, individual II:1) with complete agenesis of the corpus
      callosum, horizontal gaze palsy, progressive scoliosis, and preserved intellectual
      development.
    gene:
      preferred_term: DCC
      term:
        id: hgnc:2701
        label: DCC
    type: missense_variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28250456
      reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "DCC sequencing in a cohort of 31 patients with ACC plus interhemispheric cyst did reveal one individual (Family 3, individual II:1; Supplementary Table 1, Fig. 2c, Supplementary note) with a homozygous missense variant (c.2071C>A, p.Gln691Lys) (Fig. 2f) affecting the third fibronectin repeat."
      explanation: Identifies the homozygous missense variant c.2071C>A (p.Gln691Lys) affecting the third fibronectin repeat of DCC in Family 3.
    - reference: PMID:38585553
      reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "One patient with a homozygous DCC c.2071C>A p.(Gln691Lys) did not have intellectual disability suggesting that pathogenic missense variants may result in a milder phenotype."
      explanation: Notes that the homozygous p.Gln691Lys missense variant was associated with preserved intellectual function.
  - name: NM_005215.4:c.2399dupA (p.Asn800Lysfs*11)
    description: >-
      Homozygous 1-bp duplication in exon 16 of DCC identified in three affected siblings
      from a consanguineous Pakistani family with HGPPS2 and intellectual disability.
    gene:
      preferred_term: DCC
      term:
        id: hgnc:2701
        label: DCC
    type: frameshift_variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:33141514
      reference_title: "A novel homozygous frameshift mutation in the DCC gene in a Pakistani family with autosomal recessive horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "A hypothesis-free, unbiased exome data analysis detected an insertion of nucleotide A (c.2399dupA) in exon 16 of the DCC gene. The insertion is predicted to cause frameshift p.(Asn800Lysfs*11)."
      explanation: Documents the homozygous c.2399dupA (p.Asn800Lysfs*11) variant in exon 16 of DCC.
  - name: NM_005215.4:c.(?_1912)_(2359_?)dup (p.Ser788Tyrfs*4)
    description: >-
      Homozygous intragenic tandem duplication encompassing exons 13-15 of DCC resulting
      in a predicted frameshift p.(Ser788Tyrfs*4).
    gene:
      preferred_term: DCC
      term:
        id: hgnc:2701
        label: DCC
    type: tandem_duplication
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:38585553
      reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Exome sequencing revealed a homozygous apparently tandem duplication in the DCC (NM_005215.4):c.(?_1912)_(2359_?)dup, p.(Ser788Tyrfs*4); she has four copies of exons 13–15."
      explanation: Identifies the homozygous intragenic tandem duplication of exons 13-15 in DCC.
diagnosis:
- name: Brain Magnetic Resonance Imaging (MRI) and Diffusion Tractography
  description: >-
    Structural brain MRI and diffusion tensor tractography demonstrate the pathognomonic
    combination of complete agenesis of the corpus callosum, absence of the anterior and
    hippocampal commissures, widely spaced lateral ventricles (racing car sign), longitudinal
    Probst bundles, and a deep midline cleft throughout the brainstem with a split pons,
    butterfly-shaped medulla oblongata, and absence of the superior cerebellar peduncle
    decussation (loss of the midbrain red dot sign on color fractional anisotropy maps).
  results: >-
    Agenesis of the corpus callosum, anterior commissure, and hippocampal commissure
    together with a split pons and butterfly-shaped medulla oblongata distinguishes HGPPS2
    from ROBO3-related HGPPS1 (which has intact forebrain commissures).
  diagnosis_term:
    preferred_term: magnetic resonance imaging of brain
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In posterior fossa, pons was split in midline, and medulla oblongata showed a butterfly shape because of large midline cleft throughout the brainstem (Fig. 3). In supratentorial space, total agenesis of corpus callosum and other commissural tracts was evident. Widely spaced lateral ventricles, often called as racing car sign, could be seen."
    explanation: Describes the diagnostic supratentorial and infratentorial brain MRI hallmarks of HGPPS2.
  - reference: PMID:28250456
    reference_title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Color FA maps from our DCC(−/−) patient showed a similar failure of SCPs to decussate, as evidenced by absence of the typical midbrain “red dot” sign16 (Fig. 3c). In the pons, our patient had small middle cerebellar peduncles and also lacked evidence of transverse pontine fibers (Fig. 3c), like patients with HGPPS."
    explanation: Demonstrates diagnostic utility of diffusion tensor color fractional anisotropy maps showing absence of the midbrain decussation sign and transverse pontine fibers.

- name: Molecular Genetic Testing of DCC (Sequencing and Copy-Number Analysis)
  description: >-
    Exome or genome sequencing combined with copy-number variant (del/dup) analysis of DCC
    identifies biallelic pathogenic sequence variants or intragenic exon-level duplications
    and deletions.
  results: >-
    Detection of homozygous or compound heterozygous pathogenic variants (including
    intragenic CNVs) in DCC confirms the diagnosis of HGPPS2 and enables carrier testing
    and prenatal diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The analysis of duplications and deletions in the DCC should be included in the routine genetic diagnostic evaluation of patients with suspected HGPPS2."
    explanation: Recommends routine inclusion of DCC deletion/duplication analysis alongside sequence analysis in diagnostic evaluation.
treatments:
- name: Scoliosis Surgical Correction
  description: >-
    Spinal instrumentation and surgical fusion for severe progressive thoracic and
    thoracolumbar scoliosis in childhood or adolescence to correct spinal deformity and
    preserve truncal balance and pulmonary function.
  treatment_term:
    preferred_term: scoliosis surgical correction
    term:
      id: NCIT:C157986
      label: Spinal Fusion
  target_phenotypes:
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "She had a medical history of progressive scoliosis; at the age of 9 years, she had a thoracal scoliosis with a Cobb angle of 62° and a thoracolumbar scoliosis with a Cobb angle of 67°, which was operated. A month after the operation, she had a residual thoracal scoliosis with a Cobb angle of 15° and a thoracolumbar scoliosis with a Cobb angle of 13° (Fig. 1)."
    explanation: Documents substantial Cobb angle reduction following surgical correction of severe thoracic and thoracolumbar scoliosis in an HGPPS2 patient.

- name: Physical Therapy and Neurodevelopmental Rehabilitation
  description: >-
    Supportive physical rehabilitation and developmental therapy are used in clinical
    management to address gross motor delay, gait instability, and axial musculoskeletal
    deformity, although formal clinical outcome data on rehabilitation efficacy in HGPPS
    remain limited.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:38516134
    reference_title: "Novel variants and phenotypes of ROBO3 gene associated with horizontal gaze palsy with progressive scoliosis."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Further evaluation of the natural neurodevelopmental trajectories of HGPPS patients with pathogenic variants and their benefits from physical rehabilitation is needed in the future for precise genetic counseling and clinical management."
    explanation: Notes that while physical rehabilitation is considered in the clinical management of HGPPS spectrum disorders, systematic evaluation of its clinical benefit is still needed.

- name: Genetic Counseling
  description: >-
    Genetic counseling for affected families regarding the 25% autosomal recessive
    recurrence risk, potential mild/incomplete penetrance phenotypes (isolated mirror
    movements or callosal agenesis) in heterozygous carriers, and options for prenatal or
    preimplantation genetic testing.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38585553
    reference_title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Securing a diagnosis provides crucial information to the family for recurrence risk and allows the possibility to offer prenatal and preimplantation genetic diagnosis."
    explanation: Highlights the importance of genetic counseling for recurrence risk assessment and reproductive options in families with HGPPS2.
differential_diagnoses:
- name: Horizontal gaze palsy with progressive scoliosis 1 (ROBO3-related HGPPS1)
  description: >-
    Autosomal recessive disorder caused by biallelic pathogenic variants in ROBO3 (OMIM
    607313) that shares congenital horizontal gaze palsy, progressive childhood scoliosis,
    and a split pons with butterfly-shaped medulla oblongata. Unlike DCC-related HGPPS2,
    patients with ROBO3-related HGPPS1 have normal intelligence and intact forebrain
    commissures (normal corpus callosum, anterior commissure, and hippocampal commissure).
  distinguishing_features:
  - Intact corpus callosum, anterior commissure, and hippocampal commissures on brain MRI
  - Normal intellectual development without global neurodevelopmental delay
  - Biallelic pathogenic variants in ROBO3 rather than DCC
  disease_term:
    preferred_term: gaze palsy, familial horizontal, with progressive scoliosis 1
    term:
      id: MONDO:0020790
      label: gaze palsy, familial horizontal, with progressive scoliosis 1
  evidence:
  - reference: PMID:38516134
    reference_title: "Novel variants and phenotypes of ROBO3 gene associated with horizontal gaze palsy with progressive scoliosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "HGPPS2 (OMIM1#617542) is caused by mutations of the DCC gene and distinguished from HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures."
    explanation: Directly contrasts DCC-related HGPPS2 and ROBO3-related HGPPS1 by forebrain commissural agenesis and intellectual disability.
  - reference: PMID:29068161
    reference_title: "DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Differential genetic diagnoses for DCC-MMs include NTN1 and RAD51 (MIM# 179617) [Depienne, et al., 2012; Méneret, et al., 2014a; Méneret, et al., 2017); for DCC-iACC include CDK5RAP2 (MIM# 608201, although only one family has been described to date [Jouan, et al., 2016)); and for DSBS include ROBO3 (note: individuals with HGPPS1 do not suffer from intellectual disability and have normal forebrain commissures, consistent with the predominant role of ROBO3 in the developing hindbrain and spinal cord)"
    explanation: Identifies ROBO3-related HGPPS1 as the primary differential diagnosis for developmental split-brain syndrome (HGPPS2).
  - reference: PMID:15105459
    reference_title: "Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain axon midline crossing."
    explanation: Establishes ROBO3 mutations as the cause of hindbrain-restricted crossing defects in HGPPS1.

- name: Mirror Movements 1 and/or Agenesis of the Corpus Callosum (Monoallelic DCC Spectrum)
  description: >-
    Autosomal dominant disorder with incomplete penetrance caused by heterozygous
    loss-of-function or missense variants in DCC, presenting with isolated congenital mirror
    movements of the upper limbs, isolated partial or complete agenesis of the corpus
    callosum, or both, without horizontal gaze palsy, brainstem clefting, or progressive
    scoliosis.
  distinguishing_features:
  - Autosomal dominant (monoallelic) inheritance with incomplete penetrance
  - Absence of horizontal gaze palsy, progressive scoliosis, and midline brainstem cleft
  - Normal or near-normal neurodevelopment compared with biallelic HGPPS2
  disease_term:
    preferred_term: mirror movements 1 and/or agenesis of the corpus callosum
    term:
      id: MONDO:0100515
      label: mirror movements 1 and/or agenesis of the corpus callosum
  evidence:
  - reference: PMID:29068161
    reference_title: "DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS)."
    explanation: Distinguishes the monoallelic DCC phenotype (mirror movements and/or isolated callosal agenesis) from biallelic developmental split-brain syndrome (HGPPS2).
clinical_trials: []
datasets: []
references:
- reference: PMID:28250456
  title: "Biallelic mutations in human DCC cause developmental split-brain syndrome."
  findings:
  - statement: Biallelic loss-of-function mutations in DCC cause developmental split-brain syndrome (HGPPS2) with pan-neuraxis loss of commissural tracts.
    supporting_text: "Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported."
  - statement: Affected individuals exhibit complete agenesis of the corpus callosum, anterior commissure, and hippocampal commissure along with brainstem hypoplasia and a deep midline brainstem cleft.
    supporting_text: "MR brain imaging revealed a number of abnormalities in the affected individuals (Supplementary Table 1, Fig. 1, Supplementary Fig. 1), including ACC and absence of the anterior (AC) and hippocampal commissures (HC). Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla (Supplementary Table 1, Supplementary Fig. 1b–g)."
  - statement: Family 1 carries a homozygous 7682 bp deletion removing the 3' end of exon 1 of DCC, causing exon 1 skipping and a functional null allele; Family 2 carries homozygous c.788_794delTTTCTGG (p.Val263Alafs*36); Family 3 carries homozygous c.2071C>A (p.Gln691Lys).
    supporting_text: "A series of PCR probes (Supplementary Fig. 4b) was used to localize the precise breakpoint (Supplementary Fig. 4c), revealing a 7682 bp deletion (Fig. 2d). This deletion removed the 3′ end of exon 1, containing 61 bp of DCC coding sequence (NM_005215.3) and 7.6 kb of intronic sequence (Fig. 2d). RT-PCR from patient lymphoblasts demonstrated that this deletion causes exon 1 to be skipped entirely (Supplementary Fig. 5a–c)."
- reference: PMID:38585553
  title: "Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome."
  findings:
  - statement: Eight patients with biallelic DCC variants have been reported worldwide, with obligate horizontal gaze palsy (8/8) and midline brainstem cleft, agenesis of the corpus callosum, and absence of cerebral commissures (7/7 imaged).
    supporting_text: "Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in the brainstem, agenesis of corpus callosum, and absence of cerebral commissures present in all patients whose brain MRI result was available (N = 7/7, 100%). Common presenting features were global developmental delay, intellectual disability (N = 5/8, 63%), scoliosis (N = 7/8, 88%), short stature (N = 3/5, 60%), and behavioral problems (N = 3/5, 60%)."
  - statement: A novel homozygous intragenic tandem duplication of exons 13-15 in DCC, c.(?_1912)_(2359_?)dup p.(Ser788Tyrfs*4), causes HGPPS2, underscoring the need for copy-number analysis in diagnostic testing.
    supporting_text: "Exome sequencing revealed a homozygous apparently tandem duplication in the DCC (NM_005215.4):c.(?_1912)_(2359_?)dup, p.(Ser788Tyrfs*4); she has four copies of exons 13–15."
- reference: PMID:29068161
  title: "DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome."
  findings:
  - statement: Monoallelic DCC mutations cause congenital mirror movements and/or isolated agenesis of the corpus callosum with incomplete penetrance, whereas biallelic DCC mutations cause developmental split-brain syndrome (HGPPS2).
    supporting_text: "Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS)."
  - statement: Horizontal gaze palsy and hindbrain malformation in DSBS reflect disruption of the superior cerebellar peduncle decussation and the internuclear commissural tract linking the abducens and oculomotor nuclei.
    supporting_text: "These appear to include the decussation of the superior cerebellar peduncles (also referred to as the commissure of Wernekinck) that connects the cerebellum to the midbrain, and the commissural tract linking the lateral abducens and medial occulomotor nerves, required for conjugate horizontal eye movement"
- reference: PMID:33141514
  title: "A novel homozygous frameshift mutation in the DCC gene in a Pakistani family with autosomal recessive horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development."
  findings:
  - statement: A homozygous frameshift insertion c.2399dupA p.(Asn800Lysfs*11) in exon 16 of DCC cosegregated with autosomal recessive HGPPS2 in three siblings from a consanguineous Pakistani family.
    supporting_text: "A hypothesis-free, unbiased exome data analysis detected an insertion of nucleotide A (c.2399dupA) in exon 16 of the DCC gene. The insertion is predicted to cause frameshift p.(Asn800Lysfs*11)."
- reference: PMID:38516134
  title: "Novel variants and phenotypes of ROBO3 gene associated with horizontal gaze palsy with progressive scoliosis."
  findings:
  - statement: DCC-related HGPPS2 is clinically and radiologically distinguished from ROBO3-related HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures.
    supporting_text: "HGPPS2 (OMIM1#617542) is caused by mutations of the DCC gene and distinguished from HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures."
- reference: PMID:15105459
  title: "Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis."
  findings:
  - statement: Biallelic mutations in ROBO3 cause HGPPS1 by selectively disrupting hindbrain and spinal cord axon midline crossing while sparing forebrain commissures.
    supporting_text: "In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain axon midline crossing."
notes: >-
  Curated for issue #14107 (MONDO:0054602, OMIM:617542). HGPPS2 (developmental split-brain
  syndrome) is caused by biallelic loss-of-function variants in DCC and represents the severe
  recessive end of the DCC-related midline axon guidance spectrum, whereas heterozygous DCC
  variants cause autosomal dominant mirror movements 1 and/or agenesis of the corpus callosum
  (MONDO:0100515).

📚

References & Deep Research

References

6

PMID:28250456

Biallelic mutations in human DCC cause developmental split-brain syndrome.

3 findings

Biallelic loss-of-function mutations in DCC cause developmental split-brain syndrome (HGPPS2) with pan-neuraxis loss of commissural tracts.

"Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Affected individuals were found to possess biallelic..."

Affected individuals exhibit complete agenesis of the corpus callosum, anterior commissure, and hippocampal commissure along with brainstem hypoplasia and a deep midline brainstem cleft.

"MR brain imaging revealed a number of abnormalities in the affected individuals (Supplementary Table 1, Fig. 1, Supplementary Fig. 1), including ACC and absence of the anterior (AC) and hippocampal commissures (HC). Pons and midbrain structures were hypoplastic, and there was a large midline..."

Family 1 carries a homozygous 7682 bp deletion removing the 3' end of exon 1 of DCC, causing exon 1 skipping and a functional null allele; Family 2 carries homozygous c.788_794delTTTCTGG (p.Val263Alafs*36); Family 3 carries homozygous c.2071C>A (p.Gln691Lys).

"A series of PCR probes (Supplementary Fig. 4b) was used to localize the precise breakpoint (Supplementary Fig. 4c), revealing a 7682 bp deletion (Fig. 2d). This deletion removed the 3′ end of exon 1, containing 61 bp of DCC coding sequence (NM_005215.3) and 7.6 kb of intronic sequence (Fig. 2d)...."

PMID:38585553

Report of a Novel Homozygous Intragenic DCC Duplication and a Review of Literature of Developmental Split-Brain Syndrome aka Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development Syndrome.

2 findings

Eight patients with biallelic DCC variants have been reported worldwide, with obligate horizontal gaze palsy (8/8) and midline brainstem cleft, agenesis of the corpus callosum, and absence of cerebral commissures (7/7 imaged).

"Including the patient presented in this report, altogether 8 patients with biallelic DCC pathogenic variants have been reported in the medical literature. The hallmarks of this syndrome are the horizontal gaze palsy (N = 8/8, 100%) and typical radiological features including a midline cleft in..."

A novel homozygous intragenic tandem duplication of exons 13-15 in DCC, c.(?_1912)_(2359_?)dup p.(Ser788Tyrfs*4), causes HGPPS2, underscoring the need for copy-number analysis in diagnostic testing.

"Exome sequencing revealed a homozygous apparently tandem duplication in the DCC (NM_005215.4):c.(?_1912)_(2359_?)dup, p.(Ser788Tyrfs*4); she has four copies of exons 13–15."

PMID:29068161

DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome.

2 findings

Monoallelic DCC mutations cause congenital mirror movements and/or isolated agenesis of the corpus callosum with incomplete penetrance, whereas biallelic DCC mutations cause developmental split-brain syndrome (HGPPS2).

"Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS)."

Horizontal gaze palsy and hindbrain malformation in DSBS reflect disruption of the superior cerebellar peduncle decussation and the internuclear commissural tract linking the abducens and oculomotor nuclei.

"These appear to include the decussation of the superior cerebellar peduncles (also referred to as the commissure of Wernekinck) that connects the cerebellum to the midbrain, and the commissural tract linking the lateral abducens and medial occulomotor nerves, required for conjugate horizontal..."

PMID:33141514

A novel homozygous frameshift mutation in the DCC gene in a Pakistani family with autosomal recessive horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development.

1 finding

A homozygous frameshift insertion c.2399dupA p.(Asn800Lysfs*11) in exon 16 of DCC cosegregated with autosomal recessive HGPPS2 in three siblings from a consanguineous Pakistani family.

"A hypothesis-free, unbiased exome data analysis detected an insertion of nucleotide A (c.2399dupA) in exon 16 of the DCC gene. The insertion is predicted to cause frameshift p.(Asn800Lysfs*11)."

PMID:38516134

Novel variants and phenotypes of ROBO3 gene associated with horizontal gaze palsy with progressive scoliosis.

1 finding

DCC-related HGPPS2 is clinically and radiologically distinguished from ROBO3-related HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures.

"HGPPS2 (OMIM1#617542) is caused by mutations of the DCC gene and distinguished from HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures."

PMID:15105459

Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis.

1 finding

Biallelic mutations in ROBO3 cause HGPPS1 by selectively disrupting hindbrain and spinal cord axon midline crossing while sparing forebrain commissures.

"In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain..."

Deep Research

1

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

Claude Code ▸

Gaze Palsy, Familial Horizontal, With Progressive Scoliosis 2 (HGPPS2 / Developmental Split-Brain Syndrome): Research Report

claude-haiku-4-5-20251001, claude-opus-5-5 8 citations 2026-10-14T15:51:52.751948

Gaze Palsy, Familial Horizontal, With Progressive Scoliosis 2 (HGPPS2 / Developmental Split-Brain Syndrome): Research Report

Scope and sourcing. This report is built mainly from six references already cached in this repository: PMID:28250456, 38585553, 33141514, 29068161, 38516134 and 15105459. Quotes from them were read from the cached abstract or full text. Two web searches were also run: one for newer case reports and one for the mouse knockout paper. Anything not checked against a source is marked [unverified] and should be treated as a lead.

Several resources could not be used because they need authorization: the claude.ai PubMed, OLS, bgpt and Noctua connectors. As a result, no ontology CURIE below was looked up in this session. Every term ID is a suggested lead and must be checked with runoak, the term caches or just validate-terms before it goes into an entry.

1. Disease Information

Overview. HGPPS2 is an ultra-rare autosomal recessive disorder of axon guidance caused by biallelic loss-of-function variants in DCC, the gene for the netrin-1 receptor "deleted in colorectal carcinoma". In ROBO3-related HGPPS1, the midline-crossing failure is limited to the hindbrain and spinal cord. In HGPPS2 it affects commissures along the whole neuraxis.

Rahikkala et al. 2024 (PMID:38585553, Mol Syndromol; abstract): "Horizontal gaze palsy with progressive scoliosis-2 (HGPPS2, MIM 617542) with impaired intellectual development aka developmental split-brain syndrome is an ultra-rare congenital disorder caused by pathogenic biallelic variants in the deleted in colorectal cancer (DCC) gene."
Jamuar et al. 2017 (PMID:28250456, Nat Genet), the defining paper: "Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability."

Identifiers

Resource	ID	Status
MONDO	MONDO:0054602	already the entry's `disease_term`
OMIM	617542	quoted in PMID:38585553 and PMID:29068161
Gene (OMIM)	DCC 120470	quoted in PMID:28250456
HGNC	hgnc:2701 (DCC)	already used in the KB entry
Orphanet / ICD-10 / ICD-11 / MeSH	not checked	[unverified] ICD-10 probably falls under Q04.x/H51.0 only by analogy; do not assert it

Synonyms: HGPPS2; Horizontal gaze palsy with progressive scoliosis 2 with impaired intellectual development; Developmental split-brain syndrome (DSBS). PMID:29068161 uses "developmental split brain syndrome (DSBS, MIM# 617542)".

Data basis: aggregated case reports, about 8 published patients from 5 families. There are no registry or EHR data.

2. Etiology

Cause: biallelic germline loss-of-function variants in DCC on 18q21.2. Marsh et al. 2018 (PMID:29068161): "Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS)."
Consanguinity is a recurrent risk context: a Saudi family with first-cousin parents (PMID:28250456) and a consanguineous Pakistani family (PMID:33141514).
Environmental, protective and gene–environment factors: none reported. This is a monogenic developmental disorder.
Possible modifiers: Jamuar et al. attribute the variable mirror movements to "additional, as yet uncharacterized, background genetic modifier effects". This is speculation and is not established.

3. Phenotypes

The phenotypes below come from about 8 patients, so frequencies are qualitative. Rahikkala 2024 (PMID:38585553) summarizes them: "HGPPS2 phenotype caused by biallelic DCC variants appears to be fully penetrant and shows a similar clinical presentation including developmental delay, intellectual disability, neuromuscular scoliosis, horizontal gaze palsy, agenesis of corpus callosum, and the absence of cerebral commissures."

Phenotype	Onset / course	Frequency	Suggested HPO [verify]	Key source
Horizontal gaze palsy (no conjugate horizontal eye movements)	congenital, stable	essentially all	Horizontal gaze palsy (HP:0000641?) / Ophthalmoplegia	33141514, 28250456
Progressive scoliosis	childhood to adolescence, progressive	essentially all	Progressive scoliosis / Scoliosis HP:0002650	33141514
Global developmental delay	infancy	most	HP:0001263	28250456, 33141514
Intellectual disability	childhood, static	most (one patient described as "modest")	HP:0001249	28250456
Agenesis of the corpus callosum	congenital	all imaged	HP:0001274	28250456
Absent anterior and hippocampal commissures	congenital	Family 1 and Pakistani family	Absent anterior commissure [lookup]	28250456, 33141514
Midline brainstem cleft, "butterfly" medulla, hypoplastic pons and midbrain	congenital	Families 1 and 2	Pontine hypoplasia HP:0012110?; Brainstem dysplasia	28250456
Failed decussation of the superior cerebellar peduncles (no "red dot" sign); absent transverse pontine fibers	congenital	Family 2 (DTI)	[no specific HPO; search]	28250456
Probst bundles; widespread white-matter disorganization with low FA	congenital	Family 2 (DTI)	Abnormal cerebral white matter morphology	28250456
Mirror movements	—	variable: Family 1 proband only	Mirror movements HP:0001335?	28250456
Interhemispheric cyst	—	1 patient (missense Family 3)	Interhemispheric cyst	28250456

Supporting quotes:

Imaging, Family 1 (PMID:28250456): "Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla."
Tractography (PMID:28250456): "In place of the normal pattern of interdigitating callosal fibers, no commissural tracts were evident, either on tractography or FA maps." The same paper adds that the disorganization "was not limited to commissural fibers, but was strongly evident in associational and subcortical fibers as well."
Mirror movements (PMID:28250456): "while the proband in Family 1 exhibited mirror movements, the affected individuals in Family 2 and 3 did not."

Quality of life: no formal QoL instruments (EQ-5D, SF-36) have been reported. The functional burden comes from intellectual disability, the need for scoliosis care, and compensatory head movements for horizontal gaze. That last point is extrapolated from HGPPS1 [unverified for HGPPS2].

4. Genetic / Molecular Information

Causal gene: DCC (hgnc:2701; OMIM 120470; 18q21.2). The gene has 29 exons and encodes a 1447-amino-acid, 159 kDa single-pass transmembrane protein of the immunoglobulin superfamily, with 4 Ig and 6 fibronectin type III repeats (PMID:29068161, PMID:28250456).

Reported HGPPS2 alleles (all homozygous):

Family / origin	Variant	Class	Ref
1, Mexico (2 boys)	7,682 bp deletion removing the 3′ end of exon 1 (61 bp of coding sequence); RT-PCR shows exon 1 skipping	intragenic deletion; functional null	28250456
2, Saudi Arabia	c.788_794delTTTCTGG, p.Val263Alafs*36 (exon 4, Ig3)	frameshift	28250456
3 (ACC plus interhemispheric cyst cohort)	c.2071C>A, p.Gln691Lys (FN3 domain 3)	missense; possibly hypomorphic	28250456
Pakistan (3 sibs)	c.2399dupA, p.(Asn800Lysfs*11) (exon 16)	frameshift	33141514
Syria	c.(?1912)(2359_?)dup, p.(Ser788Tyrfs*4)	intragenic duplication	38585553

Count: "three different homozygous pathogenic frameshift variants, one homozygous missense variant, and an intragenic duplication in the DCC gene have been reported in 8 patients" (PMID:38585553).
Family 1 deletion: "Disruption of these features strongly predicts that this mutation represents a functional null." (PMID:28250456)
Possible genotype–phenotype gradient for Family 3: "This finding suggests that weaker biallelic mutations in DCC may cause milder phenotypes, although additional cases will be required to confirm this." (PMID:28250456)
Functional consequence: loss of function. All variants are germline. ClinVar classifications and gnomAD frequencies were not checked in this session. The papers state the variants are absent from ExAC, EVS, dbSNP and 1000 Genomes.
Allelic disorders of the same gene (relevant to counselling and differential diagnosis): monoallelic DCC variants cause congenital mirror movements (MRMV1, MIM 157600) and/or isolated ACC (MIM 217990), with incomplete penetrance (PMID:29068161). The LOVD locus database is https://databases.lovd.nl/shared/genes/DCC.
Copy-number testing: two of the five alleles are CNVs. Rahikkala concludes: "The analysis of duplications and deletions in the DCC should be included in the routine genetic diagnostic evaluation of patients with suspected HGPPS2."
Epigenetic or chromosomal abnormalities: none reported beyond the intragenic CNVs.

5. Environmental Information

None. There are no known environmental, lifestyle or infectious contributors. This section is not applicable.

6. Mechanism / Pathophysiology

Causal chain

Biallelic DCC loss-of-function variants (deletion, frameshift, duplication, or possibly hypomorphic missense) lead to absent or nonfunctional DCC receptor on growth cones of developing commissural axons. This is demonstrated at the RNA level for the exon-1 deletion and inferred for the other variants.
Loss of DCC results in failure to transduce netrin-1 midline attraction and long-range signalling (PMID:29068161). In the hindbrain and spinal cord, the DCC–ROBO3 complex that silences Slit repulsion is also lost (PMID:28250456: "Robo3 forms a direct molecular complex with DCC that silences repulsion from Slits … and enhances attraction to Netrins"). The human DCC–ROBO3 link is inferred from the overlap with HGPPS1 and from mouse work.
Commissural axons fail to cross the midline at every level of the neuraxis. This leads to branching consequences:
3a. Forebrain: agenesis of the corpus callosum and the anterior and hippocampal commissures. Probst bundles form instead.
3b. Brainstem: absent pontine crossing fibers and failed decussation of the superior cerebellar peduncles, producing the midline cleft or split pons and the butterfly medulla. The failure of crossing gaze pathways results in horizontal gaze palsy. The exact crossing tract has not been shown in humans; the authors write of "shared brainstem crossing defects disrupting pathways controlling conjugate gaze".
3c. Spinal cord: defective left–right interneuron circuits are thought to lead to unbalanced paraspinal muscle activity and progressive scoliosis. The authors call this speculative: "We speculate that scoliosis may pertain to unbalanced paraspinal muscle activity due to defective spinal interneuron circuits." It is supported only by Netrin-1/Dcc-deficient mice.
3d. Non-commissural white matter: broad disorganization of associational and subcortical tracts with reduced FA. A possible additional role of DCC/netrin in oligodendrocyte myelin regulation is a hypothesis only. Together these probably contribute to intellectual disability and developmental delay (inferred: "cognitive deficits may at least partially be attributable to non-commissural forebrain white matter abnormalities").
Corticospinal-tract laterality is variable. This may result in mirror movements in some patients. The mechanism is unclear; partial and complete loss of DCC may differ.

Checklist detail (term IDs to verify)

Category	Detail	Suggested terms
Pathways	Netrin-1/DCC signalling; Slit/ROBO crosstalk	GO "netrin-activated signaling pathway"; "axon midline choice point recognition"; "axon guidance" GO:0007411
Molecular function	Netrin receptor activity	GO:0005042 (already in the entry)
Cellular processes	Growth-cone guidance, commissural axon crossing, possibly myelination	GO "corpus callosum development"; "commissural neuron axon guidance"
Cell types	Commissural neurons; cortical (callosal) projection neurons; spinal commissural interneurons; possibly oligodendrocytes	CL search needed (e.g. CL:0000540 neuron is too broad; look for "commissural neuron")
Subcellular	Growth cone; plasma membrane	GO:0030426 growth cone
Metabolic, immune, omics	None reported; no transcriptomic, proteomic or single-cell data specific to the disease	—

7. Anatomical Structures Affected

Primary: CNS commissures, namely the corpus callosum, anterior commissure, hippocampal commissure, superior cerebellar peduncle decussation and transverse pontine fibers. Also the pons, midbrain and medulla oblongata.
Secondary: the vertebral column (scoliosis) and extraocular motor control.
UBERON leads [verify]: corpus callosum, anterior commissure, hippocampal commissure, pons, medulla oblongata, midbrain, superior cerebellar peduncle, cerebral white matter, vertebral column.
Laterality: midline and bilateral by nature. Scoliosis direction is not described.

8. Temporal Development

Onset: congenital. The malformation forms prenatally, and the gaze palsy is present from birth.
Progression: scoliosis appears and worsens through childhood and adolescence (PMID:33141514). Cognitive and brain-structure features are static.
Duration: lifelong. Remission is not applicable.
Critical periods: scoliosis surveillance during the growth years. The window for commissure formation is embryonic, which is the axon-guidance window, inferred from mouse data.

9. Inheritance and Population

Inheritance: autosomal recessive (HP:0000007). The Pakistani family shows co-segregation: "the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern" (PMID:33141514).
Penetrance: described as full penetrance for biallelic loss of function (PMID:38585553). Heterozygous carriers are usually unaffected but are at risk of the allelic dominant conditions (mirror movements or isolated ACC) with incomplete penetrance.
Expressivity: variable for mirror movements, and possibly milder with missense alleles.
Anticipation and germline mosaicism: none reported.
Epidemiology: about 8 patients and 5 families worldwide (Mexico, Saudi Arabia, Pakistan, Syria, and Family 3 of unstated origin). There is no prevalence or incidence figure. Use CASES_IN_LITERATURE with ULTRA_RARE.
Founder effects and carrier frequency: unknown.
Sex ratio: too few cases to estimate.

10. Diagnostics

Brain MRI and DTI. Look for the combination of agenesis of the corpus callosum, absent anterior and hippocampal commissures, a split pons, a butterfly medulla, and an absent midbrain "red dot". That combination with horizontal gaze palsy and intellectual disability points to DCC rather than ROBO3.

Genetic testing. - Exome or genome sequencing plus CNV analysis of DCC, which is mandatory because 2 of 5 alleles are CNVs. - Targeted DCC sequencing with ddPCR/qPCR for deletions or duplications. - Homozygosity mapping helps in consanguineous families. For example, the Pakistani family had loss of heterozygosity at 18q21.1–21.3 (PMID:33141514).

Other tests. Orthoptic and ocular-motility examination; spine radiographs; developmental assessment.

Differential diagnosis

Condition	Distinguishing features
HGPPS1 (ROBO3, MIM 607313)	Normal intellect, no ACC. PMID:38516134: "HGPPS2 … distinguished from HGPPS1 by impaired intellectual development, global developmental delay, agenesis of the corpus callosum, and absence of the anterior and hippocampal commissures."
Joubert syndrome	Molar-tooth sign, oculomotor apraxia [clinical knowledge]
Möbius and Duane syndromes (other congenital cranial dysinnervation disorders)	—
Isolated ACC	—
Pontine tegmental cap dysplasia	—

Screening: no newborn or population screening. Cascade carrier testing and prenatal or preimplantation testing are possible once the familial variants are known.

11. Outcome / Prognosis

No survival or mortality data. The affected patients reported were alive in childhood to young adulthood; the Pakistani family included adolescents and adults, per MeSH age tags.
Morbidity comes from intellectual disability, progressive scoliosis (which may need surgery), and the gaze limitation.
No prognostic biomarkers. The only proposed modifier of severity is allele type (null versus missense), and that is unproven.

12. Treatment

There is no disease-modifying therapy, no trial, and no pharmacogenomics. Management is supportive and draws on HGPPS1 and scoliosis practice [no HGPPS2-specific outcome data].

Intervention	Suggested NCIT term (verify)
Scoliosis bracing and spinal fusion (orthopedic surgery)	Orthopedic Surgical Procedure NCIT:C16186; therapeutic modality SURGERY
Physical, occupational and speech therapy; special education for developmental delay	Physical Therapy NCIT:C15302; Rehabilitation NCIT:C15315
Strabismus or ophthalmologic management	—
Genetic counselling	NCIT:C15240

No gene therapy, ASO or cell therapy has been developed.

13. Prevention

Primary: none.
Secondary and tertiary: spine surveillance through growth to allow early scoliosis intervention; developmental surveillance.
Counselling: 25% recurrence risk for carrier couples. Discuss carrier testing in consanguineous families and prenatal or preimplantation testing. Note the separate dominant risk to heterozygous relatives (mirror movements or isolated ACC).

14. Other Species / Natural Disease

No naturally occurring animal disease is known. OMIA was not searched [unverified].
DCC and netrin signalling is conserved from C. elegans (unc-40) and Drosophila (frazzled) to vertebrates. PMID:28250456 calls the pathway "evolutionarily conserved from C. elegans through vertebrates".

15. Model Organisms

Dcc knockout mouse. Fazeli et al. 1997, Nature 386:796–804, PMID:9126737. The PMID comes from a web search and is not cached; run just fetch-reference PMID:9126737 before citing. - Inactivating Dcc caused axonal-projection defects resembling those in netrin-1-deficient mice and had no intestinal tumour phenotype. - Jamuar notes that Netrin-1 and DCC knockout mice "are also acallosal". - Recapitulates: forebrain commissure agenesis. - Limitations: perinatal lethality is commonly reported [unverified], which limits study of scoliosis and cognition. Brainstem crossing defects are "less consistently predicted from animal studies" (PMID:28250456). - Fidelity: high for ACC, low or unknown for gaze palsy and scoliosis.

Netrin-1–deficient mice. These show disrupted spinal left–right interneuron circuits and are the basis of the scoliosis hypothesis (PMID:28250456, refs 29–30; primary PMIDs [not retrieved]).

Zebrafish dcc mutants. These show hindbrain startle-circuit abnormalities (PMID:28250456; primary PMID [not retrieved]).

Kanga (Dcc^kanga) mouse. A spontaneous allele that removes the P3 intracellular domain and causes corticospinal and spinal midline defects with a hopping gait. This is a [lead, unverified].

Other systems: no iPSC or organoid model of HGPPS2 has been reported.

Gaps and recommendations for curation

Fetch and cite PMID:9126737 for the mouse model. Search for primary PMIDs for the Netrin-1 interneuron, zebrafish and kanga papers.
Look up every HPO, GO, CL, UBERON and NCIT term listed above. None were checked in this session because the OLS connector needs authorization.
No case reports after 2024 were found in a standard web search. The count of about 8 patients is current as of PMID:38585553.
The mechanism behind scoliosis and the specific gaze-pathway tract are hypotheses. Model them with directness: INDIRECT or as an EMERGING mechanistic hypothesis rather than as established edges.
The existing KB entry, kb/disorders/Gaze_Palsy_Familial_Horizontal_With_Progressive_Scoliosis_2.yaml, already cites five of the six references above.

Sources - Jamuar et al. 2017, PMID:28250456 — https://www.nature.com/articles/ng.3804.pdf - Rahikkala et al. 2024, PMID:38585553 — https://www.utupub.fi/items/21c918e6-1e57-4076-bbcd-562f429bd836/full ; https://oulurepo.oulu.fi/handle/10024/48657 ; https://research.utu.fi/converis/portal/detail/Publication/380543436 - Zaka et al. 2021, PMID:33141514 (cached abstract) - Marsh et al. 2018, PMID:29068161 (cached) - Xie et al. 2024, PMID:38516134 (cached) - Jen et al. 2004, PMID:15105459 (cached) - Fazeli et al. 1997, PMID:9126737 — https://www.nature.com/articles/386796a0 ; https://pesquisa.bvsalud.org/ses/resource/es/mdl-9126737 ; https://wi.mit.edu/news/deleted-colorectal-cancer-dcc-gene-plays-role-wiring-mouse-brain-and-spinal-cord

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	7
Resolved	7
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	7
On topic	6
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	17
Resolved	17
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	7
Terms named correctly	1
Terms named as a different term	4
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0054602 (1 mention) - the report calls it "MONDO"; MONDO calls it gaze palsy, familial horizontal, with progressive scoliosis, 2
HP:0001263 (1 mention) - the report calls it "most"; HP calls it Global developmental delay
HP:0001249 (1 mention) - the report calls it "most (one patient described as "modest")"; HP calls it Intellectual disability
GO:0005042 (1 mention) - the report calls it "already in the entry"; GO calls it netrin receptor activity

Terms whose name is worth a second look

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

HP:0001274 (1 mention) - the report calls it "all imaged"; HP calls it Agenesis of corpus callosum, and lists "Callosal agenesis" among its other names
NCIT:C15240 (1 mention) - the report calls it "Genetic counselling"; NCIT calls it Genetic Counseling

Gaze_Palsy_Familial_Horizontal_With_Progressive_Scoliosis_2

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Gaze Palsy, Familial Horizontal, With Progressive Scoliosis 2 (HGPPS2 / Developmental Split-Brain Syndrome): Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Gaps and recommendations for curation

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look