Arhinia, choanal atresia, and microphthalmia

Summary

Arhinia, choanal atresia, and microphthalmia (MONDO:0011323) is a disease caused by SMCHD1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SMCHD1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 49
• Phenotypes (HPO): 32

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000518	Cataract	Very frequent (80-99%)
HP:0000692	Tooth malposition	Very frequent (80-99%)
HP:0003241	External genital hypoplasia	Very frequent (80-99%)
HP:0004409	Hyposmia	Very frequent (80-99%)
HP:0006352	Failure of eruption of permanent teeth	Very frequent (80-99%)
HP:0008736	Hypoplasia of penis	Very frequent (80-99%)
HP:0009927	Aplasia of the nose	Very frequent (80-99%)
HP:0009932	Single naris	Very frequent (80-99%)
HP:0040326	Hypoplasia of the olfactory bulb	Very frequent (80-99%)
HP:0100596	Absent nares	Very frequent (80-99%)
HP:0000023	Inguinal hernia	Very frequent (80-99%)
HP:0000135	Hypogonadism	Very frequent (80-99%)
HP:0000309	Abnormal midface morphology	Very frequent (80-99%)
HP:0000458	Anosmia	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000044	Hypogonadotropic hypogonadism	Frequent (30-79%)
HP:0000327	Hypoplasia of the maxilla	Frequent (30-79%)
HP:0000453	Choanal atresia	Frequent (30-79%)
HP:0000528	Anophthalmia	Frequent (30-79%)
HP:0000568	Microphthalmia	Frequent (30-79%)
HP:0000572	Visual loss	Frequent (30-79%)
HP:0000612	Iris coloboma	Frequent (30-79%)
HP:0000618	Blindness	Frequent (30-79%)
HP:0000646	Amblyopia	Frequent (30-79%)
HP:0000771	Gynecomastia	Frequent (30-79%)
HP:0009023	Abdominal wall muscle weakness	Frequent (30-79%)
HP:0009924	Aplasia/Hypoplasia involving the nose	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000176	Submucous cleft hard palate	Occasional (5-29%)
HP:0000193	Bifid uvula	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0030752	Dacryocystocele	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	arhinia, choanal atresia, and microphthalmia
Mondo ID	MONDO:0011323
MeSH	C537429
OMIM	603457
Orphanet	1135, 2250
SNOMED CT	720511000
UMLS	C1863878
MedGen	355084
GARD	0027263
Is cancer (heuristic)	no

Also known as: arhinia choanal atresia microphthalmia · arhinia, choanal atresia, microphthalmia, and hypogonadotropic hypogonadism · arrhinia-choanal atresia-microphthalmia syndrome · BAM syndrome · BAMS · Bosma Arhinia Microphthalmia Syndrome · Bosma arhinia microphthalmia syndrome · Bosma arhinia-microphthalmia syndrome · Bosma Henkin Christiansen syndrome · Bosma syndrome · Bosma-Henkin-Christiansen syndrome · congenital absence of nose and anterior nasopharynx · Gifford-Bosma syndrome · hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome · Ruprecht Majewski syndrome

Data availability: 49 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome without intellectual disability › arhinia, choanal atresia, and microphthalmia

Related subtypes (167): Treacher-Collins syndrome, branchio-oto-renal syndrome, acrorenal syndrome, Townes-Brocks syndrome, Ascher syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, branchiooculofacial syndrome, Gordon syndrome, cataract-aberrant oral frenula-growth delay syndrome, cherubism, Alagille syndrome, cleft palate-lateral synechia syndrome, blepharocheilodontic syndrome, craniofacial-deafness-hand syndrome, cryptomicrotia-brachydactyly-excess fingertip arch syndrome, Beare-Stevenson cutis gyrata syndrome, Cyprus facial-neuromusculoskeletal syndrome, deafness-craniofacial syndrome, short stature-valvular heart disease-characteristic facies syndrome, 3-M syndrome, external auditory canal atresia-vertical talus-hypertelorism syndrome, femoral-facial syndrome, multinodular goiter-cystic kidney-polydactyly syndrome, hand-foot-genital syndrome, Bencze syndrome, oculoauriculovertebral spectrum with radial defects, Holt-Oram syndrome, mullerian duct anomalies-limb anomalies syndrome, Aase-Smith syndrome, LADD syndrome, Noonan syndrome with multiple lentigines, median nodule of the upper lip, Nager acrofacial dysostosis, Marshall syndrome, Binder syndrome, Schilbach-Rott syndrome, nasopalpebral lipoma-coloboma syndrome, autosomal dominant prognathism, short stature-craniofacial anomalies-genital hypoplasia syndrome, radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome, scalp-ear-nipple syndrome, flat face-microstomia-ear anomaly syndrome, Czeizel-Losonci syndrome, otospondylomegaepiphyseal dysplasia, autosomal dominant, ventricular extrasystoles with syncopal episodes-perodactyly-robin sequence syndrome, posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome, acrofacial dysostosis, Weyers type, Freeman-Sheldon syndrome, Ackerman syndrome, acro-renal-mandibular syndrome, acrocraniofacial dysostosis, PAGOD syndrome, alar cartilages hypoplasia-coloboma-telecanthus syndrome, microcephaly-albinism-digital anomalies syndrome, fetal akinesia deformation sequence, Cooper-Jabs syndrome, Barber-Say syndrome, Beemer-Ertbruggen syndrome, blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome, camptodactyly syndrome, Guadalajara type 1, camptodactyly syndrome, Guadalajara type 2, heart defects-limb shortening syndrome, Verloove Vanhorick-Brubakk syndrome, Juberg-Hayward syndrome, heart defect - tongue hamartoma - polysyndactyly syndrome, Fraser syndrome, split hand-foot malformation 1 with sensorineural hearing loss, von Voss-Cherstvoy syndrome, autosomal recessive faciodigitogenital syndrome, gingival fibromatosis-facial dysmorphism syndrome, Fibulo-ulnar hypoplasia-renal anomalies syndrome, frontofacionasal dysplasia, genito-palato-cardiac syndrome, Hirschsprung disease-hearing loss-polydactyly syndrome, Holzgreve-Wagner-Rehder syndrome, hydrocephaly-tall stature-joint laxity syndrome, McKusick-Kaufman syndrome, acrofrontofacionasal dysostosis 2, Vici syndrome, Donohue syndrome, Dahlberg-Borer-Newcomer syndrome, macrosomia-microphthalmia-cleft palate syndrome, mesomelic dwarfism-cleft palate-camptodactyly syndrome, Nijmegen breakage syndrome, lethal congenital contracture syndrome 1, Richieri Costa-da Silva syndrome, Keipert syndrome, nephrosis-deafness-urinary tract-digital malformations syndrome, ichthyosis-oral and digital anomalies syndrome, otoonychoperoneal syndrome, PHAVER syndrome, polysyndactyly-cardiac malformation syndrome, postaxial acrofacial dysostosis, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, renal-genital-middle ear anomalies, Richieri Costa-Pereira syndrome, SHORT syndrome, tetraamelia-multiple malformations syndrome, thymic-renal-anal-lung dysplasia, trigonocephaly-bifid nose-acral anomalies syndrome, white forelock with malformations, syndactyly-telecanthus-anogenital and renal malformations syndrome, Abruzzo-Erickson syndrome, CHILD syndrome, pentalogy of Cantrell, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, short tarsus-absence of lower eyelashes syndrome, PARC syndrome, CODAS syndrome, pectus excavatum-macrocephaly-dysplastic nails syndrome, velo-facial-skeletal syndrome, anophthalmia plus syndrome, van den Ende-Gupta syndrome, absent tibia-polydactyly-arachnoid cyst syndrome, diaphragmatic defect-limb deficiency-skull defect syndrome, cleft lip/palate-intestinal malrotation-cardiopathy syndrome, Matthew-Wood syndrome, microcephaly-cardiac defect-lung malsegmentation syndrome, dislocation of the hip-dysmorphism syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, grange syndrome, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, anonychia-microcephaly syndrome, developmental malformations-deafness-dystonia syndrome, lethal congenital contracture syndrome 2, craniolenticulosutural dysplasia, 8q22.1 microdeletion syndrome, Braddock syndrome, choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome, BNAR syndrome, Frias syndrome, lethal congenital contracture syndrome 3, Fontaine progeroid syndrome, microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, Nijmegen breakage syndrome-like disorder, Warsaw breakage syndrome, even-plus syndrome, split-foot malformation-mesoaxial polydactyly syndrome, anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome, digitotalar dysmorphism, heart-hand syndrome type 2, night blindness-skeletal anomalies-dysmorphism syndrome, Charlie M syndrome, facial dysmorphism-anorexia-cachexia-eye and skin anomalies syndrome, cleft lip-retinopathy syndrome, Cole-Carpenter syndrome, progressive non-infectious anterior vertebral fusion, dysmorphism-pectus carinatum-joint laxity syndrome, Hirschsprung disease-type D brachydactyly syndrome, mandibuloacral dysplasia, contractures - webbed neck - micrognathia - hypoplastic nipples syndrome, Thomas syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, branchiootic syndrome, auricular abnormalities-cleft lip with or without cleft palate-ocular abnormalities syndrome, Axenfeld-Rieger syndrome, macrostomia-preauricular tags-external ophthalmoplegia syndrome, pelvis syndrome, Fanconi anemia, van der Woude syndrome, hypertrichosis-acromegaloid facial appearance syndrome, 49,XYYYY syndrome, congenital vertebral-cardiac-renal anomalies syndrome, structural heart defects and renal anomalies syndrome, Greig cephalopolysyndactyly-contiguous gene syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

49 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 15 pathogenic, 13 benign, 2 likely benign, 2 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
375761	NM_015295.3(SMCHD1):c.1043A>G (p.His348Arg)	SMCHD1	Pathogenic	no assertion criteria provided
375762	NM_015295.3(SMCHD1):c.423G>C (p.Leu141Phe)	SMCHD1	Pathogenic	no assertion criteria provided
375763	NM_015295.3(SMCHD1):c.1199A>T (p.Gln400Leu)	SMCHD1	Pathogenic	no assertion criteria provided
375765	NM_015295.3(SMCHD1):c.410G>A (p.Gly137Glu)	SMCHD1	Pathogenic	no assertion criteria provided
375766	NM_015295.3(SMCHD1):c.403A>T (p.Ser135Cys)	SMCHD1	Pathogenic	no assertion criteria provided
375767	NM_015295.3(SMCHD1):c.404G>A (p.Ser135Asn)	SMCHD1	Pathogenic	criteria provided, single submitter
431461	NM_015295.3(SMCHD1):c.320T>C (p.Leu107Pro)	SMCHD1	Pathogenic	no assertion criteria provided
431462	NM_015295.3(SMCHD1):c.386T>A (p.Met129Lys)	SMCHD1	Pathogenic	no assertion criteria provided
431463	NM_015295.3(SMCHD1):c.415A>C (p.Asn139His)	SMCHD1	Pathogenic	no assertion criteria provided
431464	NM_015295.3(SMCHD1):c.423G>T (p.Leu141Phe)	SMCHD1	Pathogenic	no assertion criteria provided
431466	NM_015295.3(SMCHD1):c.725C>G (p.Ala242Gly)	SMCHD1	Pathogenic	no assertion criteria provided
431467	NM_015295.3(SMCHD1):c.1259A>T (p.Asp420Val)	SMCHD1	Pathogenic	no assertion criteria provided
431468	NM_015295.3(SMCHD1):c.1417G>C (p.Glu473Gln)	SMCHD1	Pathogenic	no assertion criteria provided
431469	NM_015295.3(SMCHD1):c.1568C>A (p.Thr523Lys)	SMCHD1	Pathogenic	no assertion criteria provided
431470	NM_015295.3(SMCHD1):c.1571A>G (p.Asn524Ser)	SMCHD1	Pathogenic	no assertion criteria provided
375768	NM_015295.3(SMCHD1):c.404G>T (p.Ser135Ile)	SMCHD1	Likely pathogenic	criteria provided, single submitter
282418	NM_015295.3(SMCHD1):c.1655G>A (p.Arg552Gln)	SMCHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
375764	NM_015295.3(SMCHD1):c.408A>C (p.Glu136Asp)	SMCHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030486	NM_015295.3(SMCHD1):c.1504C>G (p.Pro502Ala)	SMCHD1	Uncertain significance	criteria provided, single submitter
1055874	NM_015295.3(SMCHD1):c.4316A>G (p.Asn1439Ser)	SMCHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1959429	NM_015295.3(SMCHD1):c.3067C>T (p.Pro1023Ser)	SMCHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2384008	NM_015295.3(SMCHD1):c.5041A>G (p.Thr1681Ala)	SMCHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431390	NM_015295.3(SMCHD1):c.5572A>G (p.Thr1858Ala)	SMCHD1	Uncertain significance	criteria provided, single submitter
2705561	NM_015295.3(SMCHD1):c.5912T>G (p.Leu1971Trp)	SMCHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2724672	NM_015295.3(SMCHD1):c.3803C>T (p.Ser1268Phe)	SMCHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
282094	NM_015295.3(SMCHD1):c.3527_3528inv (p.Thr1176Met)	SMCHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
282095	NM_015295.3(SMCHD1):c.3527C>T (p.Thr1176Ile)	SMCHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
288633	NM_015295.3(SMCHD1):c.1186C>A (p.Gln396Lys)	SMCHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
375760	NM_015295.3(SMCHD1):c.1034A>G (p.Gln345Arg)	SMCHD1	Uncertain significance	criteria provided, single submitter
431465	NM_015295.3(SMCHD1):c.511T>G (p.Phe171Val)	SMCHD1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SMCHD1	Definitive	Autosomal dominant	arhinia, choanal atresia, and microphthalmia	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMCHD1	Orphanet:2250	Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
SMCHD1	Orphanet:269	Facioscapulohumeral dystrophy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMCHD1	HGNC:29090	ENSG00000101596	A6NHR9	Structural maintenance of chromosomes flexible hinge domain-containing protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMCHD1	Structural maintenance of chromosomes flexible hinge domain-containing protein 1	Non-canonical member of the structural maintenance of chromosomes (SMC) protein family that plays a key role in epigenetic silencing by regulating chromatin architecture.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMCHD1	Other/Unknown	no		SMC_hinge, SMC_hinge_sf, HATPase_C_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMCHD1	290	ubiquitous	marker	calcaneal tendon, colonic epithelium, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMCHD1	1,888

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMCHD1	A6NHR9	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nose development	1	2407.4×	0.002	SMCHD1
autosome genomic imprinting	1	2407.4×	0.002	SMCHD1
dosage compensation by inactivation of X chromosome	1	1532.0×	0.002	SMCHD1
positive regulation of double-strand break repair via nonhomologous end joining	1	991.3×	0.002	SMCHD1
random inactivation of X chromosome	1	936.2×	0.002	SMCHD1
negative regulation of double-strand break repair via homologous recombination	1	624.1×	0.002	SMCHD1
chromosome organization	1	581.1×	0.002	SMCHD1
positive regulation of DNA repair	1	358.6×	0.003	SMCHD1
double-strand break repair	1	203.0×	0.005	SMCHD1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMCHD1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SMCHD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SMCHD1	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	SMCHD1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	SMCHD1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.