General

Apert syndrome

• Mechanism of disease: FGFR2 gene; Autosomal dominant inheritance; Most cases are de novo with a paternal age effect described.

• Clinical features: Multisuture craniosynostosis (often coronal), midface retrusion, characteristic syndactyly of hands/feet; cleft palate can occur.

• Diagnosis / Work-up: Clinical suspicion of craniosynostosis with typical syndactyly pattern; Confirmation by molecular testing identifying a pathogenic variant in FGFR2.

• Management: Multidisciplinary craniofacial care; staged cranial vault/craniosynostosis surgery; hand/foot surgery as indicated; monitor airway/OSA, feeding, hearing/vision, dental/orthodontic needs; developmental supports/therapies as needed.

Alport syndrome

• Mechanism of disease: COL4A5 (X-linked), COL4A3/COL4A4 (AR or AD), rare digenic; X-linked most common; also AR/AD; ~10-15% of male probands with X-linked Alport may be de novo.

• Clinical features: Persistent hematuria → proteinuria → progressive kidney disease/ESKD; sensorineural hearing loss; ocular findings (e.g., anterior lenticonus, retinal changes).

• Diagnosis / Work-up: Clinical suspicion from family history + hematuria and/or progressive kidney disease ± hearing/ocular findings; Confirmation by pathogenic variant in COL4A3/4/5 (preferred); kidney biopsy can support diagnosis when molecular testing is non-diagnostic.

• Management: Early nephrology involvement; RAAS blockade (ACEi/ARB) to reduce proteinuria and delay progression; audiology/ophthalmology surveillance; renal replacement planning if needed; cascade testing and family counseling.

Coffin-Lowry syndrome (RPS6KA3-related ID spectrum)

• Mechanism of disease: RPS6KA3 gene; X-linked inheritance; ~2/3 de novo; remainder inherited (maternal carrier or mosaicism).

• Clinical features: Intellectual disability (often more severe in males), hypotonia, stimulus-induced drop episodes, characteristic facial/hand findings, skeletal anomalies (kyphoscoliosis), possible hearing loss, dental issues, sleep apnea.

• Diagnosis / Work-up: Clinical suspicion from classic phenotype in a male (or variably affected female); Confirmation by molecular testing identifying a pathogenic variant in RPS6KA3.

• Management: Symptom-directed care: developmental/educational supports; evaluation and management of drop episodes/seizures; monitor/manage scoliosis and orthopedic issues; audiology, dental, and sleep evaluation (OSA); multidisciplinary long-term follow-up.

Dystrophic epidermolysis bullosa (DEB)

• Mechanism of disease: COL7A1 gene; Autosomal dominant (DDEB) or autosomal recessive (RDEB) depending on variant pattern; De novo can occur (rate varies; not the defining feature).

• Clinical features: Skin fragility with blistering/erosions from minor trauma; scarring and milia; nail dystrophy; mucosal involvement; in severe RDEB: chronic wounds, mitten deformities, strictures, malnutrition, and markedly increased SCC risk.

• Diagnosis / Work-up: Clinical suspicion from compatible blistering/scarring pattern; Confirmation by molecular testing showing biallelic COL7A1 pathogenic variants (RDEB) or heterozygous COL7A1 pathogenic variant (DDEB); skin biopsy with IF mapping/TEM if molecular testing is inconclusive or unavailable.

• Management: Wound care and infection prevention; pain/itch control; nutrition support; surveillance for complications (contractures, strictures, anemia, SCC in severe forms); PT/OT; multidisciplinary EB center care when possible.

Hutchinson-Gilford progeria syndrome (HGPS)

• Mechanism of disease: LMNA gene; Autosomal dominant inheritance; ~98% de novo; ~2% due to parental gonadal mosaicism.

• Clinical features: Postnatal-onset growth failure, lipodystrophy, alopecia, characteristic facies, skeletal changes (e.g., coxa valga), progressive cardiovascular disease (major driver of morbidity/mortality), typically normal intellect.

• Diagnosis / Work-up: Clinical suspicion from characteristic phenotype emerging in early childhood with normal intellectual development; Confirmation by pathogenic variant in LMNA (molecular testing accompanies clinical diagnosis).

• Management: Cardiovascular risk surveillance and management; supportive multidisciplinary care (nutrition, PT/OT, orthopedic management); lonafarnib is described targeted therapy associated with improved outcomes; avoid injury-risk settings and dehydration/high fever given cardio/cerebrovascular risks; family counseling re: low but non-zero recurrence risk (mosaicism).

Malignant hyperthermia (susceptibility)

• Mechanism of disease: Most commonly RYR1; also CACNA1S (others exist); Typically autosomal dominant susceptibility; De novo not emphasized for routine risk assessment (family-based susceptibility is common).

• Clinical features: Life-threatening hypermetabolic crisis triggered by certain volatile anesthetics and/or succinylcholine: hypercarbia, muscle rigidity, tachycardia, hyperthermia, rhabdomyolysis.

• Diagnosis / Work-up: Clinical diagnosis (episode): Use of a clinical grading scale can help determine likelihood of MH event; Definitive susceptibility testing: In vitro contracture testing (caffeine-halothane contracture test / IVCT) and/or molecular genetic testing in an appropriate clinical context.

• Management: Acute: Immediate discontinuation of triggers; dantrolene; aggressive supportive care (cooling, manage acidosis/hyperkalemia/rhabdomyolysis) | Preventive: Avoid triggering anesthetics; anesthesiology plan with "non-triggering" agents; family evaluation/cascade testing when a causative variant is identified.

Treacher Collins syndrome

• Mechanism of disease: TCOF1 (most common), POLR1D, POLR1C; Often autosomal dominant (e.g., TCOF1; some POLR1D), and autosomal recessive forms exist (e.g., POLR1C); De novo.

• Clinical features: Craniofacial anomalies: malar hypoplasia, micrognathia, downslanting palpebral fissures, external ear anomalies; conductive hearing loss common; cleft palate may occur; intelligence usually normal.

• Diagnosis / Work-up: Clinical suspicion from classic craniofacial pattern ± hearing loss; Confirmation by molecular testing identifying a pathogenic variant in one of the associated genes.

• Management: Multidisciplinary craniofacial management; airway/feeding support (especially infancy); audiology evaluation and hearing rehabilitation; staged reconstructive surgeries; speech therapy if cleft palate/velopharyngeal issues; psychosocial support.

Autosomal recessive polycystic kidney disease (ARPKD)

• Mechanism of disease: PKHD1 gene; Autosomal recessive inheritance; De novo not typical (classically inherited AR).

• Clinical features: Enlarged echogenic kidneys, cystic dilation of collecting ducts; variable neonatal respiratory compromise; congenital hepatic fibrosis/portal HTN and biliary disease may develop.

• Diagnosis / Work-up: Clinical suspicion from prenatal/postnatal imaging with enlarged echogenic kidneys ± oligohydramnios; liver involvement features (CHF/portal HTN); Confirmation by molecular testing showing biallelic pathogenic variants in PKHD1.

• Management: Nephrology/hepatology co-management; manage HTN and CKD complications; respiratory support in severe neonatal disease; surveillance and management for portal HTN and cholangitis risk; dialysis/transplant planning (kidney ± liver depending on phenotype).

Branchiootorenal (BOR) spectrum disorder

• Mechanism of disease: EYA1 (most common), SIX1, SIX5; Autosomal dominant inheritance; De novo occurs.

• Clinical features: Branchial arch anomalies (branchial cleft fistula/cysts), ear malformations and hearing loss, renal anomalies (ranging from mild dysplasia to severe malformations).

• Diagnosis / Work-up: Clinical suspicion from combination of branchial anomalies + otologic/hearing findings ± renal anomalies; Confirmation by molecular testing identifying a pathogenic variant in a BOR-associated gene; renal imaging and audiology are core components of work-up.

• Management: Audiology evaluation and hearing rehabilitation; renal surveillance/management (nephrology as needed); surgical management of branchial anomalies; multidisciplinary follow-up and cascade testing for relatives.

Campomelic dysplasia

• Mechanism of disease: SOX9 gene; Autosomal dominant inheritance; Most are de novo (classically).

• Clinical features: Bowing of long bones (especially tibiae/femora), skeletal dysplasia, characteristic facies; often life-threatening respiratory compromise; frequent sex development differences (e.g., undervirilization/sex reversal in some 46,XY individuals).

• Diagnosis / Work-up: Clinical suspicion from prenatal ultrasound or postnatal skeletal findings + characteristic phenotype; Confirmation by molecular testing identifying a pathogenic variant affecting SOX9 (or regulatory regions depending on case).

• Management: Intensive neonatal/respiratory support when needed; orthopedic management; evaluation/management of DSD with endocrine/urology team; anticipatory guidance for high morbidity/mortality; family counseling regarding typically de novo occurrence.

Hypochondroplasia

• Mechanism of disease: FGFR3 (vast majority); Autosomal dominant inheritance; Can be inherited or arise de novo.

• Clinical features: Mild short-limb disproportionate short stature; stocky build; relative macrocephaly; radiographic skeletal dysplasia features; variable learning issues reported.

• Diagnosis / Work-up: Clinical suspicion from mild disproportionate short stature + supportive radiographic findings; Confirmation by molecular testing identifying a pathogenic variant in FGFR3.

• Management: Growth/orthopedic monitoring; manage complications (spinal stenosis symptoms, orthopedic issues); developmental/learning evaluation if concerns; genetic counseling regarding AD inheritance and variable expressivity.

Pendred syndrome (SLC26A4-related SNHL spectrum)

• Mechanism of disease: SLC26A4 gene; Autosomal recessive inheritance; Occasional de novo events.

• Clinical features: Sensorineural hearing loss (often childhood onset; can be fluctuating/progressive), enlarged vestibular aqueduct (EVA) ± cochlear malformations; thyroid goiter often later (commonly 2nd decade), thyroid dysfunction variable.

• Diagnosis / Work-up: Consensus (historical) clinical criteria: SNHL + EVA (± cochlear/vestibular malformations) + iodide organification defect (goiter may or may not be present); Current confirmation: Biallelic pathogenic variants in SLC26A4 on molecular testing; temporal bone imaging (CT/MRI) and thyroid evaluation (US; labs for management rather than for "goiter diagnosis").

• Management: Audiology care (hearing aids/cochlear implant as indicated), speech/language supports; counsel to avoid head trauma/barotrauma that can worsen hearing in EVA; thyroid ultrasound surveillance for goiter and manage thyroid function clinically; genetic counseling and sibling testing when appropriate.

Proteus syndrome (AKT1-related overgrowth spectrum)

• Mechanism of disease: AKT1 (classically mosaic; recurrent p.Glu17Lys described); Not inherited in typical cases (post-zygotic somatic mosaicism); De novo (arises randomly early in development).

• Clinical features: Progressive, segmental/asymmetric overgrowth (bones, connective tissue, skin), cerebriform connective tissue nevus, vascular malformations, lipomas; increased risk of DVT/PE.

• Diagnosis / Work-up: Clinical diagnostic criteria: clinical scoring system; diagnosis requires compatible phenotype plus detection of a mosaic AKT1 pathogenic variant (often from affected tissue rather than blood).

• Management: Multidisciplinary care (orthopedics, dermatology, vascular anomalies, rehab). Surveillance/low threshold for evaluation of thrombosis/PE; management of overgrowth and deformities (often staged). Symptom-directed treatment of vascular lesions, tumors, and functional impairment.

Simpson-Golabi-Behmel syndrome (SGBS type 1)

• Mechanism of disease: GPC3 (most common); X-linked (classically affects males; females variably affected); De novo reported; can be inherited from a carrier mother or mosaicism.

• Clinical features: Prenatal/postnatal overgrowth (macrosomia), coarse facial features, macroglossia/macrostomia, congenital anomalies (cardiac, renal), variable ID; increased risk of embryonal tumors (notably Wilms tumor, hepatoblastoma).

• Diagnosis / Work-up: Clinical suspicion based on overgrowth + congenital anomalies + characteristic craniofacies; confirm with molecular testing for a pathogenic variant in GPC3 (and related genes when indicated).

• Management: Multisystem evaluation (cardiology, nephrology, developmental). Tumor surveillance (e.g., abdominal US-based screening protocols may be recommended depending on age/risk profile). Supportive therapies for development, feeding, and congenital anomalies.

Sturge-Weber syndrome

• Mechanism of disease: GNAQ somatic mosaic variant (classically post-zygotic); Sporadic (not typically inherited); De novo (post-zygotic somatic [mosaic]).

• Clinical features: Facial port-wine birthmark, leptomeningeal vascular malformation (angioma), seizures/stroke-like episodes, developmental impacts; glaucoma common (often ipsilateral to facial lesion).

• Diagnosis / Work-up: Clinical recognition + neuroimaging (brain MRI with contrast typically used to evaluate leptomeningeal involvement) + ophthalmologic evaluation for glaucoma; neurologic assessment for seizures.

• Management: Seizure management (neurology), glaucoma treatment (ophthalmology), developmental supports; pulsed-dye laser often used for port-wine stain in clinical practice; ongoing multidisciplinary surveillance for neurologic/ophthalmic complications.

Thrombocytopenia with absent radius (TAR) syndrome

• Mechanism of disease: RBM8A---typically a compound mechanism: a 1q21.1 deletion involving one RBM8A allele plus a low-expression/noncoding variant on the other allele; Inheritance: "AR-like/complex" (requires two contributing alleles); De novo: The deletion component can be de novo or inherited; overall recurrence depends on parental carrier status.

• Clinical features: Bilateral absent radius with thumbs present, thrombocytopenia presenting in infancy (often improves with age), bleeding risk; can have additional anomalies and cow's milk intolerance in some.

• Diagnosis / Work-up: Clinical pattern recognition + platelet counts; confirmatory genetic testing for 1q21.1 deletion and RBM8A variant(s).

• Management: Bleeding precautions; platelet transfusions/supportive hematology care during severe thrombocytopenia; avoid platelet-inhibiting meds when possible; orthopedic/hand surgery and PT/OT for limb function; family counseling depends on whether parents carry the deletion and/or the RBM8A hypomorphic allele.

Hermansky-Pudlak syndrome (HPS)

• Mechanism of disease: Multiple genes (e.g., HPS1, HPS3, etc.; subtype-dependent); Autosomal recessive inheritance; De novo not typical for AR disorders.

• Clinical features: Oculocutaneous albinism + bleeding diathesis (platelet storage pool defect); some subtypes have pulmonary fibrosis, granulomatous colitis, and/or immunodeficiency.

• Diagnosis / Work-up: Clinical findings (OCA + bleeding history) + platelet function/dense granule evaluation when used + molecular confirmation with biallelic pathogenic variants in an HPS gene.

• Management: Bleeding management planning (procedure precautions; avoid aspirin/NSAIDs when advised), ophthalmology/vision supports and sun protection; surveillance for pulmonary fibrosis (pulmonology) and colitis (GI) in at-risk subtypes; multidisciplinary long-term monitoring.

Kabuki syndrome

• Mechanism of disease: KMT2D (AD) and KDM6A (X-linked); Inheritance: AD (KMT2D) or X-linked (KDM6A); De novo: Likely high for KMT2D.

• Clinical features: Distinctive facial gestalt, developmental delay/ID, postnatal growth issues, hypotonia; congenital heart defects, skeletal anomalies, persistent fetal fingertip pads; can include immune dysfunction and hearing loss.

• Diagnosis / Work-up: Clinical recognition + confirmatory molecular testing in KMT2D/KDM6A; targeted evaluations for cardiac, hearing, renal, immune/endocrine issues.

• Management: Multidisciplinary management: cardiology for CHD, audiology/hearing supports, feeding/ENT support, developmental/educational therapies; address immune issues when present; routine surveillance guided by organ involvement.

Rubinstein-Taybi syndrome (RSTS)

• Mechanism of disease: CREBBP (most), EP300 (subset); Autosomal dominant inheritance; Most cases are de novo.

• Clinical features: Broad thumbs and great toes, characteristic facial features, short stature, moderate-severe ID; may have congenital heart/kidney anomalies, ocular findings, feeding issues, and increased tendency toward keloids.

• Diagnosis / Work-up: Clinical diagnosis supported by molecular testing (sequence + del/dup) of CREBBP and EP300; evaluate for heart, kidney, eye, and developmental issues.

• Management: Supportive care with developmental services; management of congenital anomalies (cardiac/renal), ophthalmology, hearing/ENT, feeding/GERD; behavioral and educational planning; genetic counseling regarding AD inheritance and mostly de novo occurrence.

Bardet-Biedl syndrome (BBS)

• Mechanism of disease: BBS1, BBS10, BBS2, BBS14 (also known as IFT27), ARL6 (BBS3), and MKKS; Usually autosomal recessive inheritance; De novo not typical for AR disorders.

• Clinical features: Retinal cone-rod dystrophy (progressive vision loss), obesity/metabolic complications, postaxial polydactyly, cognitive/learning issues, hypogonadotropic hypogonadism/genitourinary anomalies, renal malformations/disease.

• Diagnosis / Work-up: Clinical criteria (age-dependent features) + molecular confirmation via multigene panel/exome; baseline/ongoing evaluation of vision, renal function/imaging, endocrine/metabolic profile, and GU anomalies.

• Management: Vision supports/low-vision services; structured obesity and metabolic management; renal surveillance and nephrology care; endocrinology for hypogonadism/diabetes risk; educational supports; family testing and AR recurrence counseling.

Thanatophoric dysplasia

• Mechanism of disease: FGFR3 gene; Autosomal dominant inheritance; Majority de novo.

• Clinical features: Severe skeletal dysplasia with extremely short limbs, narrow thorax/short ribs with pulmonary hypoplasia, macrocephaly; typically lethal in perinatal period though rare longer survival reported.

• Diagnosis / Work-up: Prenatal ultrasound findings (lethal skeletal dysplasia pattern) with molecular confirmation of FGFR3 variant when desired; postnatal radiographs + molecular confirmation if liveborn.

• Management: Often focuses on perinatal counseling and palliative planning given lethality; if liveborn, intensive respiratory support may be attempted, with multidisciplinary decision-making. Recurrence risk usually low but theoretical germline mosaicism discussed.

Cornelia de Lange syndrome (CdLS)

• Mechanism of disease: Multiple cohesin-pathway genes (commonly NIPBL; also SMC1A, HDAC8, RAD21, SMC3, etc.); Inheritance: Often autosomal dominant (e.g., NIPBL), some X-linked (e.g., SMC1A); De novo: Many cases de novo (varies by gene).

• Clinical features: Prenatal/postnatal growth restriction, characteristic facial features (e.g., synophrys), upper limb anomalies, ID/developmental delay, feeding/GERD, congenital anomalies (cardiac/GU), behavioral phenotype.

• Diagnosis / Work-up: Clinical diagnosis supported by standardized clinical scoring approaches in practice; confirm via multigene testing for CdLS-associated genes. Work-up typically includes growth/nutrition, cardiac, hearing/vision, GI/GERD evaluation, and developmental assessment.

• Management: Multidisciplinary care: feeding and reflux management, growth/nutrition support, developmental therapies, hearing/vision surveillance, management of congenital anomalies, behavioral supports; genetic counseling tailored to gene/inheritance and mosaicism considerations.

Congenital adrenal hyperplasia (focus: 21-hydroxylase deficiency)

• Mechanism of disease: CYP21A2 (21-hydroxylase deficiency accounts for ~95% of CAH); Autosomal recessive inheritance; De novo not typical for AR (though new variants can arise rarely).

• Clinical features: Impaired cortisol synthesis → elevated ACTH and adrenal hyperplasia; androgen excess → virilization; in classic forms: possible salt-wasting crisis (aldosterone deficiency) and ambiguous genitalia in 46,XX; nonclassic forms: hyperandrogenism later.

• Diagnosis / Work-up: Newborn screening (elevated 17-hydroxyprogesterone) and confirmatory hormonal testing ± ACTH stimulation; electrolytes/renin assessment in suspected salt-wasting; molecular testing of CYP21A2 supports confirmation and genotype-phenotype counseling.

• Management: Lifelong endocrine management: glucocorticoid replacement, mineralocorticoid + salt in salt-wasting forms, stress-dose education, emergency planning; monitor growth, BP, electrolytes, androgen control, and puberty/fertility issues; individualized counseling about genital management where relevant.

Incontinentia pigmenti (IP)

• Mechanism of disease: IKBKG (NEMO); X-linked dominant; often male-lethal (most surviving affected individuals are female; rare affected males occur); De novo: Common (many simplex cases).

• Clinical features: Ectodermal/neuroectodermal disorder affecting skin/hair/teeth/nails/eyes/CNS. Skin lesions evolve through stages (vesicular → verrucous → hyperpigmented whorls → hypopigmented/atrophic lines). Ocular and CNS complications can be clinically significant.

• Diagnosis / Work-up: Clinical pattern (stage-wise lesions often along Blaschko lines) + molecular confirmation of IKBKG pathogenic variant; prompt ophthalmologic exam due to risk of retinal involvement; neurologic assessment if seizures or developmental concerns.

• Management: Early and ongoing ophthalmology surveillance, dermatology support (skin care; infection prevention in vesicular stage), dental follow-up for tooth anomalies, neurologic monitoring/management (seizures, developmental therapies), and genetic counseling regarding X-linked inheritance and recurrence risk (including possibility of maternal mosaicism).

Bloom syndrome

• Mechanism of disease: BLM (RecQ helicase); Autosomal recessive. De novo concept not typically applicable for AR (affected individuals have biallelic pathogenic variants).

• Clinical features: Severe pre/postnatal growth deficiency, photosensitivity, immune abnormalities, insulin resistance, and markedly increased early-onset cancer risk.

• Diagnosis / Work-up: Clinical suspicion based on growth + sun-sensitive facial rash + recurrent infections/cancer predisposition; confirm with molecular testing identifying biallelic BLM pathogenic variants (and/or characteristic cytogenetic instability testing when used).

• Management: Rigorous cancer surveillance/early evaluation, aggressive management of infections, sun protection, and monitoring for metabolic complications (e.g., insulin resistance/diabetes). Genetic counseling and carrier testing in at-risk relatives.

Meckel-Gruber syndrome (Meckel syndrome)

• Mechanism of disease: Genetically heterogeneous ciliopathy; pathogenic variants in ~16 genes reported. Typically autosomal recessive inheritance (as part of nephronophthisis-related ciliopathies spectrum).

• Clinical features: Classic triad: cystic kidney disease, occipital encephalocele/CNS malformation, postaxial polydactyly; may include hepatic abnormalities/fibrosis, oligohydramnios sequence, and other anomalies; often pre- or perinatally lethal.

• Diagnosis / Work-up: Usually suspected prenatally by ultrasound (renal cystic enlargement, encephalocele, polydactyly ± oligohydramnios). Confirm when possible with molecular testing using a ciliopathy/MKS gene panel or exome/genome, plus careful phenotype review.

• Management: Primarily supportive/perinatal palliative planning given lethality in many cases; multidisciplinary counseling (MFM, neonatology, genetics). Recurrence risk counseling consistent with AR inheritance.

Fryns syndrome

• Mechanism of disease: Autosomal recessive.

• Clinical features: Major features: congenital diaphragmatic defects/hernia, characteristic coarse facial appearance, distal digital hypoplasia (short terminal phalanges/small nails), pulmonary hypoplasia, and multiple congenital anomalies (ocular, clefting, renal, CNS, cardiac, GI, genital).

• Diagnosis / Work-up: Clinical suspicion in neonate/fetus with CDH + typical facial/digital findings + multisystem anomalies; work-up includes detailed anomaly evaluation, exclusion of chromosomal/CNV causes, and molecular testing when indicated (e.g., PIGN and/or broader testing given heterogeneity).

• Management: Immediate neonatal management for CDH (intubation, surgical/supportive care) and tailored management of associated anomalies with multidisciplinary follow-up; seizure management when present; ongoing surveillance after successful CDH repair in specialized centers.

Sotos syndrome

• Mechanism of disease: NSD1 pathogenic variant or deletion. Autosomal dominant. ~95% de novo; ~5% inherited from an affected parent.

• Clinical features: Cardinal triad: distinctive facial appearance + overgrowth (height/OFC ≥2 SD) + learning disability/developmental delay. Additional features can include behavioral findings (incl. ASD), advanced bone age, cardiac/renal anomalies, scoliosis, seizures.

• Diagnosis / Work-up: Diagnosis suspected clinically from triad and supportive findings; confirmed by molecular testing identifying NSD1 pathogenic variant/deletion.

• Management: Symptom-based: developmental/educational supports; screen/manage organ-specific issues (cardiac/renal, orthopedic, neurologic). Provide recurrence-risk counseling considering high de novo proportion, with attention to rare parental mosaicism.

Osteogenesis imperfecta (COL1A1/COL1A2-related)

• Mechanism of disease: COL1A1 / COL1A2 (type I collagen). For this subtype: autosomal dominant. Many probands are simplex due to de novo variants; parental mosaicism reported (up to ~16%).

• Clinical features: Core: fractures with minimal trauma, variable dentinogenesis imperfecta, and hearing loss (often later). Severity ranges from mild fracture predisposition to perinatal lethality depending on type/variant.

• Diagnosis / Work-up: Diagnosis based on clinical/radiographic pattern and confirmed by molecular testing (*COL1A1/COL1A2*). Distinguish from non-collagen OI types and non-accidental trauma where relevant.

• Management: Multidisciplinary bone health (orthopedics, PT/OT), fracture prevention, mobility supports, dental care for DI, hearing surveillance, and consideration of pharmacologic bone strengthening when indicated. Genetic counseling includes recurrence risk and mosaicism discussion.

Aarskog-Scott syndrome (FGD1-related faciogenital dysplasia)

• Mechanism of disease: FGD1. X-linked inheritance. ~10% de novo in affected males reported.

• Clinical features: Typical findings: short stature (often), facial features, shawl scrotum/genital anomalies, and digital anomalies; variable expression, with many heterozygous females asymptomatic or mildly affected.

• Diagnosis / Work-up: Clinical criteria exist but are not universally standardized; in current practice, diagnosis is typically confirmed by identifying a pathogenic variant in FGD1.

• Management: Supportive care (growth/developmental supports as needed; management of genital/orthopedic issues), plus family testing and counseling regarding X-linked risks, including testing of mother and at-risk relatives.

VACTERL association

• Mechanism of disease: Etiology often unknown; typically considered sporadic/multifactorial rather than single-gene with predictable inheritance (term "association" reflects nonrandom co-occurrence).

• Clinical features: Defined by congenital anomalies with ≥3 of: Vertebral, Anal atresia, Cardiac, Tracheo-esophageal fistula/esophageal atresia, Renal, Limb anomalies. Additional anomalies can occur.

• Diagnosis / Work-up: Diagnosis is clinical, based on meeting component criteria; evaluation includes systematic screening for each component (spine imaging, echocardiogram, renal ultrasound, assessment for TEF/EA and limb anomalies).

• Management: Management is anomaly-directed, often surgical (e.g., anal atresia/TEF/EA, cardiac defects), plus renal and orthopedic follow-up and coordinated multidisciplinary care; genetic evaluation often performed to exclude overlapping syndromes.

Usher syndrome

• Mechanism of disease: Genetically heterogeneous. Commonly autosomal recessive (e.g., USH1/USH2). De novo variants can occur at low rate in AR conditions; counseling typically AR.

• Clinical features: Combined hearing loss + progressive vision loss due to retinitis pigmentosa. USH1: congenital profound SNHL + vestibular areflexia; USH2: congenital moderate-severe SNHL, RP onset later, vestibular often normal/variable.

• Diagnosis / Work-up: Diagnosis based on audiologic testing + ophthalmologic evidence of RP ± vestibular testing, with confirmation via molecular genetic testing (Usher gene panels/exome).

• Management: Hearing rehabilitation (hearing aids/cochlear implant as appropriate), low-vision supports, educational accommodations, mobility training, and ongoing ophthalmologic/audiologic surveillance. Genetic counseling and carrier testing for relatives when familial variants known

Joubert syndrome

• Mechanism of disease: Predominantly autosomal recessive; occasionally X-linked (e.g., OFD1-related) or rarer dominant patterns in select genes.

• Clinical features: Neurodevelopmental disorder with variable multi-system involvement; classically includes hypotonia/ataxia, developmental delay, abnormal eye movements; associated retinal dystrophy, renal/hepatic disease can occur (variable by subtype).

• Diagnosis / Work-up: Diagnosis requires characteristic neuroimaging finding (molar tooth sign on brain MRI) plus clinical features; confirm with molecular testing (ciliopathy/JBTS gene panel or exome/genome), and evaluate for retinal/renal/hepatic involvement.

• Management: Supportive multidisciplinary care: developmental therapies, ophthalmology, nephrology/hepatology surveillance depending on subtype, and management of breathing abnormalities/seizures when present; genetic counseling primarily AR.

Rett syndrome (MECP2 disorders)

• Mechanism of disease: MECP2. X-linked. >99% simplex, most due to de novo pathogenic variants (or parental germline mosaicism).

• Clinical features: Almost exclusively affects females; period of apparently normal early development followed by regression, loss of purposeful hand skills with hand stereotypies, impaired communication, gait abnormalities, seizures, breathing irregularities, and deceleration of head growth in many cases.

• Diagnosis / Work-up: Clinical diagnosis supported by classic phenotype/regression pattern; confirmation with MECP2 molecular testing.

• Management: Symptom-focused supportive care: neurology (seizures), feeding/nutrition, PT/OT, communication supports, breathing/sleep management, orthopedic monitoring (scoliosis), and coordinated long-term multidisciplinary follow-up.

Cystic fibrosis

• Mechanism of disease: CFTR. Autosomal recessive.

• Clinical features: Progressive multisystem disease with thick mucus, chronic sinopulmonary disease, pancreatic insufficiency/malabsorption, and other complications; variable severity.

• Diagnosis / Work-up: Diagnosis via newborn screen (where available) plus confirmatory testing (classically sweat chloride) and/or CFTR molecular testing with clinical correlation; evaluation includes pulmonary, pancreatic, nutritional assessments.

• Management: Multidisciplinary CF center care: airway clearance, infection management, nutritional/pancreatic enzyme replacement as needed, and genotype-directed CFTR modulator therapy for eligible variants.

Stickler syndrome

• Mechanism of disease: Genes vary by type: common AD forms due to COL2A1, COL11A1, COL11A2 (heterozygous); AR forms due to COL9A1/2/3 (biallelic). De novo can occur in AD forms; proportion unknown.

• Clinical features: Connective tissue disorder with ocular issues (high myopia, cataract, retinal detachment risk), hearing loss (conductive and/or sensorineural), midface hypoplasia and cleft palate/Pierre Robin sequence, and early-onset degenerative joint disease.

• Diagnosis / Work-up: Diagnosis based on characteristic clinical findings plus confirmation with molecular testing of relevant collagen genes; assess eyes, hearing, craniofacial/palate, and joints.

• Management: Key management is prevention/early detection of complications: regular ophthalmology with retinal detachment vigilance, hearing evaluation/support, management of cleft palate/PRS by craniofacial team, and orthopedic/rheumatologic support for early arthritis.

GJB2-Related Non-Syndromic Hearing Loss

• Mechanism of disease: GJB2 (connexin 26). Typically AR; biallelic pathogenic variants cause congenital/early-onset hearing loss. De novo rate not a dominant driver (most cases are inherited AR).

• Clinical features: Bilateral SNHL, variable severity; usually non-syndromic (no consistent extra-auditory findings).

• Diagnosis / Work-up: Audiology (ABR/behavioral testing), evaluate for syndromic clues; confirm with molecular testing (targeted GJB2 or hearing-loss panel).

• Management: Early intervention: hearing aids, cochlear implant candidacy evaluation, speech/language therapy, educational accommodations; monitor communication development.

Alagille Syndrome

• Mechanism of disease: JAG1 (majority) and NOTCH2. AD. De novo is common (often cited ~50-70% in clinical references; clinical diagnosis and gene-based confirmation).

• Clinical features: Multisystem: cholestasis / bile duct paucity, cardiac (often peripheral pulmonary stenosis, TOF), characteristic facies, vertebral anomalies (e.g., butterfly vertebrae), ocular findings (e.g., posterior embryotoxon), possible renal/vascular issues; variable expressivity.

• Diagnosis / Work-up: Clinical diagnostic criteria can establish diagnosis; alternatively confirm with heterozygous pathogenic variant in JAG1/NOTCH2. Work-up: LFTs/cholestasis evaluation, cardiac echo, ophthalmology, spine imaging, renal assessment.

• Management: Treat cholestasis/pruritus, optimize nutrition and fat-soluble vitamins, manage cardiac lesions, monitor growth and renal/vascular complications; liver transplant for progressive liver failure/intractable complications.

Ectodermal Dysplasia (focused: Hypohidrotic ED)

• Mechanism of disease: Most commonly EDA (often XLR), also EDAR, EDARADD, WNT10A (can be AD/AR). De novo rate varies by gene/family; multiple inheritance patterns are recognized.

• Clinical features: Classic triad: hypohidrosis/anhidrosis (heat intolerance), hypotrichosis (sparse hair), hypodontia/anodontia with conical teeth; characteristic facies, dry skin/eczema, recurrent respiratory issues from mucosal dryness.

• Diagnosis / Work-up: Diagnosis may be clinical (ectodermal structure findings) + dental assessment; confirm with molecular testing of EDA/EDAR/EDARADD/WNT10A when possible; family history helps infer inheritance.

• Management: Heat avoidance/cooling strategies, manage skin (emollients/eczema care), ENT/pulmonary care as needed; early and ongoing dental rehabilitation (prosthodontics/implants), speech support if dental issues affect articulation.

Ataxia-Telangiectasia

• Mechanism of disease: ATM. AR. De novo not typical for affected individuals (biallelic). Heterozygote carrier frequency estimated about 1 in 200.

• Clinical features: Progressive childhood-onset cerebellar ataxia, oculo-cutaneous telangiectasias, immunodeficiency/recurrent sinopulmonary infections, elevated malignancy risk (esp. leukemia/lymphoma). Prevalence ~1/40,000-100,000.

• Diagnosis / Work-up: Work-up: neurologic exam, immunologic evaluation (Ig levels/lymphocyte subsets), AFP often elevated, radiosensitivity; confirm with ATM molecular testing (and/or functional assays where used).

• Management: Supportive multidisciplinary care: infection prevention/treatment (immunology; IVIG in selected cases), PT/OT/speech/swallow support, monitor/mitigate malignancy risk; avoid unnecessary ionizing radiation when feasible due to radiosensitivity.

Ehlers-Danlos Syndrome (Classical type as representative "EDS")

• Mechanism of disease: COL5A1 / COL5A2 most common for classical EDS (cEDS). AD. ~50% de novo among diagnosed individuals (roughly half inherited, half de novo).

• Clinical features: cEDS: skin hyperextensibility, atrophic scarring, generalized joint hypermobility, easy bruising/tissue fragility.

• Diagnosis / Work-up: Clinical suspicion based on skin + joint findings; confirm with molecular testing identifying a pathogenic variant in COL5A1/COL5A2 (supports subtype classification).

• Management: Joint protection, PT focused on stabilization/proprioception, wound care strategies and surgical planning for tissue fragility; assess for hernias/prolapse; individualized pain management.

Hypermobile Ehlers-Danlos Syndrome (hEDS)

• Mechanism of disease: Gene not definitively established for most cases; inheritance pattern in families consistent with AD in many. De novo rate not well established due to absent single-gene confirmation.

• Clinical features: Generalized joint hypermobility with chronic musculoskeletal pain, subluxations/dislocations, fatigue; associated features can include autonomic symptoms and mild cardiac findings in some cohorts (e.g., MVP reported in studies).

• Diagnosis / Work-up: Clinical diagnosis using published criteria (2017 framework is the common standard referenced in clinics). Rule out other heritable connective tissue disorders with targeted testing when indicated.

• Management: PT/rehab (stabilization, pacing), activity modification, pain management (multimodal), treat comorbid dysautonomia/GI symptoms when present; psychosocial support for chronic illness burden.

Oculocutaneous Albinism (OCA -- genetically heterogeneous)

• Mechanism of disease: Multiple genes (e.g., TYR (OCA1), OCA2 (OCA2), others). Typically AR. De novo rate not usually emphasized; biallelic inheritance is typical.

• Clinical features: Reduced melanin in skin/hair + ocular features: nystagmus, reduced visual acuity, foveal hypoplasia, photophobia, strabismus; increased sunburn/skin cancer risk.

• Diagnosis / Work-up: Ophthalmologic exam (including foveal development), dermatologic assessment; confirm with molecular testing (albinism panel) to define subtype and counsel recurrence risk.

• Management: Sun protection and regular dermatology surveillance; optimize vision with low-vision services, refractive correction, tinted lenses; educational accommodations and visual aids.

Familial Dysautonomia

• Mechanism of disease: ELP1 (historically IKBKAP). AR. De novo not typical (biallelic inheritance). High carrier frequency in Ashkenazi Jewish populations (classic estimate ~1 in 30).

• Clinical features: Sensory and autonomic neuropathy: feeding/GI dysmotility, BP instability, absent/decreased tears (alacrima), vomiting crises, altered pain/temperature perception, recurrent respiratory complications.

• Diagnosis / Work-up: Confirm with molecular testing (founder variant testing in at-risk populations; full sequencing if needed). Clinical evaluation of autonomic function, swallowing/aspiration risk, growth/nutrition, pulmonary status.

• Management: Supportive, multidisciplinary: nutritional/feeding management, treatment of autonomic crises, pulmonary hygiene and aspiration prevention, PT/OT, monitoring for scoliosis and complications; genetic counseling and carrier screening in high-risk groups.

Familial Mediterranean Fever (FMF)

• Mechanism of disease: MEFV (pyrin). Classically AR; pseudo-dominant patterns can occur in high-carrier populations and variable penetrance is recognized. De novo not typical.

• Clinical features: Recurrent self-limited inflammatory attacks: fever + serositis (abdominal, chest), arthritis, rash; risk of AA amyloidosis if untreated.

• Diagnosis / Work-up: Diagnosis often clinical + ethnicity/family history; confirm with MEFV testing (targeted variants or sequencing). Monitor urine protein/renal function for amyloidosis risk; inflammatory markers during attacks.

• Management: Colchicine is first-line to prevent attacks and amyloidosis; IL-1 inhibitors in colchicine-resistant/intolerant cases in specialist care; renal surveillance.

Achondroplasia

• Mechanism of disease: FGFR3. AD. ~80% de novo pathogenic variant rate.

• Clinical features: Disproportionate short stature (rhizomelia), macrocephaly with frontal bossing, midface hypoplasia, hypotonia in infancy; risk of craniocervical junction compression, sleep-disordered breathing, otitis media.

• Diagnosis / Work-up: Diagnosis often clinical + radiographic features; confirm with FGFR3 testing when needed (e.g., atypical cases or prenatal evaluation).

• Management: Anticipatory surveillance: foramen magnum stenosis, hydrocephalus, apnea/OSA, hearing/ENT issues; growth/orthopedic management; family counseling re recurrence risk (including paternal age association for de novo).

Fragile X Syndrome

• Mechanism of disease: FMR1 CGG repeat expansion (>200 = full mutation with methylation/silencing). X-linked. Not typically "de novo" in the usual sense; full mutations commonly arise via maternal transmission from a premutation allele expansion (ACMG describes multi-step expansion across generations). Expands when passed down by women. Gray = 45-54, Premutation 55-200.

• Clinical features: ID/developmental delay (often more severe in males), ASD features, anxiety/ADHD, characteristic facies in some; macroorchidism post-puberty in males. Frequency ~1/4,000 males and ~1/8,000 females.

• Diagnosis / Work-up: Confirm by FMR1 CGG repeat analysis (PCR ± Southern/methylation assessment depending on lab approach). Assess neurodevelopment, behavior, and associated medical issues; offer family testing for premutation/full mutation.

• Management: Early intervention (speech/OT/PT), individualized education plans, behavioral therapy, targeted pharmacotherapy for ADHD/anxiety/seizures as indicated; genetic counseling including premutation-associated risks (FXTAS/FXPOI).

McCune-Albright Syndrome (MAS) / Fibrous Dysplasia-MAS spectrum

• Mechanism of disease: GNAS, post-zygotic mosaic activating variants. Not inherited (sporadic). De novo occurs after conception; vertical transmission not observed.

• Clinical features: Triad spectrum: polyostotic fibrous dysplasia, café-au-lait macules, endocrine hyperfunction (e.g., precocious puberty; thyroid, GH excess; others). Phenotype depends on tissue distribution of mosaicism.

• Diagnosis / Work-up: Often clinical; imaging for fibrous dysplasia (radiographs/CT/MRI as indicated), endocrine evaluation. Molecular confirmation can be challenging due to mosaicism (testing affected tissue may be required).

• Management: Multidisciplinary: endocrine-directed therapy (e.g., manage precocious puberty, thyroid/GH excess), orthopedic management of fractures/deformity, pain management; surveillance tailored to involved organs.

Androgen Insensitivity Syndrome (AIS)

• Mechanism of disease: AR (androgen receptor). X-linked. De novo occurs in a subset; many cases are inherited from a heterozygous mother, but new pathogenic variants are also described.

• Clinical features: Spectrum depends on residual androgen sensitivity (complete/partial/mild). Phenotype can include typical female external genitalia in 46,XY (complete AIS), or undervirilized genitalia/ambiguous genitalia (partial AIS), or mild undervirilization/infertility in some.

• Diagnosis / Work-up: Consider in 46,XY DSD presentation; evaluation commonly includes endocrine assessment and confirmation with molecular testing of AR; karyotype and targeted hormonal testing are standard clinical elements.

• Management: Multidisciplinary DSD care (endocrinology, genetics, psychology, urology/gynecology). Individualized decisions regarding pubertal management, gonadal management/tumor risk counseling, and fertility counseling; psychosocial support is central.

Waardenburg Syndrome

• Mechanism of disease: Most commonly PAX3, MITF, SOX10, EDNRB, EDN3, SNAI2 (genetic heterogeneity). Inheritance: Usually autosomal dominant; a minority are due to new variants (de novo) in families without prior history.

• Clinical features: Congenital or early-onset hearing loss and pigmentation changes (hair/skin/eyes), including heterochromia or very pale blue eyes; phenotypic range varies by subtype.

• Diagnosis / Work-up: Clinical recognition (hearing + pigmentary findings ± subtype features) with confirmation by molecular testing when available; audiologic evaluation is core.

• Management: Hearing management (early audiology, hearing aids/cochlear implant evaluation as appropriate), ophthalmology evaluation as indicated, and supportive services (speech/language, educational accommodations). Genetic counseling for subtype-specific inheritance.

Craniosynostosis Syndromes (syndromic craniosynostosis group)

• Mechanism of disease: Common genes / patterns: FGFR-related craniosynostosis (often AD; includes multiple syndromic entities) and other craniosynostosis genes such as FGFR3 (Muenke; AD), TWIST1 (Saethre-Chotzen; AD), and EFNB1 (craniofrontonasal; X-linked). De novo: Frequently seen in AD craniosynostosis syndromes; exact rates vary by gene/syndrome.

• Clinical features: Premature suture fusion (often coronal in Muenke; variable across syndromes), characteristic craniofacial patterns, and syndrome-specific associated features (hearing loss can occur in some; limb findings can accompany certain syndromes).

• Diagnosis / Work-up: Clinical craniofacial exam + imaging (often CT or equivalent craniofacial imaging per clinical practice) + targeted evaluation for airway/feeding/vision/hearing. Confirmation typically by gene panel testing (craniosynostosis panel) or targeted testing when phenotype suggests a specific syndrome.

• Management: Craniofacial team management: surgical planning when indicated, monitoring for intracranial pressure/vision issues, hearing evaluation, airway/feeding support when relevant, developmental surveillance, and syndrome-specific follow-up.

Pierre Robin Sequence (PRS)

• Mechanism of disease: Etiology often unknown/heterogeneous; can be isolated or occur as part of syndromes (e.g., connective tissue disorders like Stickler). No single inheritance pattern for "PRS" as a category.

• Clinical features: Triad/sequencing features: micrognathia, glossoptosis, and airway obstruction; cleft palate is common but may not be required for diagnosis (source notes disagreement).

• Diagnosis / Work-up: Clinical diagnosis based on characteristic craniofacial and airway findings, with evaluation of feeding/airway and assessment for syndromic features (including genetics referral if indicated).

• Management: Airway stabilization and feeding support in infancy (often coordinated by neonatology/ENT/craniofacial teams), cleft palate management when present, and developmental monitoring. Evaluate for underlying syndromes when suggested by family history or additional findings.

Cleft Lip/Palate

• Mechanism of disease: Etiology commonly multifactorial (genetic + environmental); can also be part of numerous syndromes. Inheritance/de novo: Not a single-gene condition in most cases; syndromic forms follow their underlying genetic mechanism.

• Clinical features: Orofacial clefting involving lip and/or palate; complications can include feeding difficulties, speech issues, and recurrent ear infections.

• Diagnosis / Work-up: Usually clinical at birth (or prenatal ultrasound in some cases). Work-up includes assessment for additional anomalies (to determine isolated vs syndromic) and referral to a cleft/craniofacial team; genetics evaluation when syndromic features are present.

• Management: Multidisciplinary cleft team care: feeding strategies, surgical repair planning, speech therapy, audiology/ENT for otitis media/hearing, dental/orthodontic follow-up, and psychosocial support.

Holoprosencephaly (HPE)

• Mechanism of disease: Genes: Heterogeneous; commonly includes SHH, ZIC2, SIX3, TGIF1 among others; can be syndromic or nonsyndromic. Inheritance: Often autosomal dominant with variable penetrance in nonsyndromic forms; de novo rates vary by gene (e.g., higher de novo proportion for ZIC2 than SHH).

• Clinical features: Spectrum of forebrain cleavage defects with variable craniofacial findings; severity ranges widely, and some relatives may have mild "microforms."

• Diagnosis / Work-up: Neuroimaging (prenatal and/or postnatal) to define brain malformation pattern; genetics work-up often includes chromosomal testing/CNV evaluation and multigene sequencing panels for HPE genes when appropriate.

• Management: Multidisciplinary care tailored to severity (neurology, endocrinology if pituitary involvement, feeding/airway support, developmental services). Genetic counseling should address variable expressivity and gene-specific de novo/inheritance patterns.

Epilepsy Syndromes (DEPDC5, KCNQ2, SCN1A)

• Mechanism of disease: DEPDC5: AD focal epilepsies; often familial; some have focal cortical dysplasia/hemimegalencephaly. KCNQ2: AD spectrum from self-limited neonatal epilepsy to neonatal-onset DEE (DEE forms often de novo). SCN1A: AD seizure disorders including Dravet syndrome/GEFS+ spectrum; de novo is common in severe presentations.

• Clinical features: DEPDC5: focal seizures, variable severity, many with normal MRI but subset with malformations. KCNQ2: neonatal-onset seizures (often first week) with variable developmental outcome (more severe in DEE). SCN1A: early-onset febrile and afebrile seizures with broad phenotypic range; Dravet is a key severe phenotype.

• Diagnosis / Work-up: Epilepsy evaluation (EEG, MRI as indicated) plus molecular testing (epilepsy gene panel/exome) to define etiology and support syndrome classification.

• Management: Neurology-led management with syndrome-informed antiseizure therapy selection, developmental support services as indicated, and family counseling (including recurrence risk and testing of relatives where relevant, especially for familial focal epilepsies such as DEPDC5).

Familial Hypercholesterolemia (FH)

• Mechanism of disease: Genes: LDLR, APOB, PCSK9 (classic AD FH). Inheritance: Autosomal dominant; biallelic disease (HoFH) causes earlier/more severe phenotype. De novo: Can occur but most cases are familial AD.

• Clinical features: Elevated LDL-C, tendon xanthomas in some, and increased risk for premature atherosclerotic cardiovascular disease; severity greater with biallelic disease.

• Diagnosis / Work-up: Lipid profile (LDL-C elevation), family history, clinical criteria commonly used in practice, and confirmatory genetic testing when available/appropriate (also supports cascade testing).

• Management: Lifestyle counseling plus lipid-lowering pharmacotherapy (e.g., statin-based regimens in standard care), and escalation strategies for severe disease; systematic family-based testing and prevention counseling

L1CAM-associated hydrocephalus (L1 syndrome)

• Mechanism of disease: L1CAM. X-linked; predominantly affects males. De novo: Can be inherited through maternal line; de novo variants also occur.

• Clinical features: Spectrum with hallmark findings including hydrocephalus, variable intellectual disability, spasticity of the legs, and adducted thumbs.

• Diagnosis / Work-up: Clinical suspicion in congenital hydrocephalus (especially with adducted thumbs/spasticity pattern) with confirmation by molecular testing of L1CAM; neuroimaging and neurologic assessment guide phenotype delineation.

• Management: Neurosurgical management for hydrocephalus (e.g., shunting per clinical need), developmental and rehabilitation therapies, spasticity management, and coordinated long-term neurologic support. Genetic counseling focuses on X-linked inheritance and maternal carrier testing.

MTHFR (clinically relevant entity: MTHFR deficiency / homocystinuria due to MTHFR deficiency)

• Mechanism of disease: MTHFR. Autosomal recessive for true enzymatic deficiency disorders.

• Clinical features (deficiency): Biochemical pattern includes hyperhomocysteinemia due to impaired folate-dependent metabolism; clinical manifestations depend on severity and age of onset (metabolic disorder framework).

• Diagnosis / Work-up: Biochemical testing (homocysteine-based evaluation in appropriate clinical contexts) plus confirmatory molecular testing for pathogenic variants in MTHFR for suspected true deficiency; interpret common-variant testing cautiously and in clinical context.

• Management: Management is specialist-directed (typically metabolic/genetics) and includes targeted metabolic therapy approaches for true deficiency disorders. For common-variant testing, results do not automatically explain elevated homocysteine and other causes (e.g., vitamin status, other conditions) may be relevant.