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| Intellectual disability v11.9 | SEC31A |
Ida Ertmanska changed review comment from: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp). Unaffected parents confirmed het.; to: PMID: 39725565 Almontashiri et al., 2025 Female proband; parents are first cousins. IUGR and multiple congenital anomalies were seen on the antenatal scan. She was born very small, with dysmorphic facial features. She had hypotonia with hyperreflexia, but no seizures. Head ultrasound revealed absent CC and an interhemispheric cyst. She had short bowed limbs, contractures, Wormian skull bones, shortening of the long bones, and microcephaly. She died at 15 days old due to bradycardia. Solo WES revealed a homozygous SEC31A splice variant c.1435-1G>A. Splice AI score is Splice-Altering / strong (1) for this variant. RT-PCR showed exon skipping and overall reduction in SEC31A expression. PMID: 40508110 AlTassan et al., 2025 Report of a 5yo male proband with global developmental delay, seizure disorder, hypotonia, spasticity, dysphagia, dysmorphic features, and bilateral hearing loss. Growth parameters indicated microcephaly, failure to thrive, and short stature. He was born to consanguineous parents. WES and WGS showed a homozygous SEC31A variant (c.1359C>G, p.Cys453Trp) - variant not in gnomAD v4.1.1. Unaffected parents confirmed het. Parents confirmed to be consanguineous, Arab ethnicity. PMID: 30464055 Halperin et al., 2018 2 Bedouin sibs from a consanguineous family. The syndromic presenation included IUGR, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness, optic nerve atrophy with no eye fixation, bilateral cataracts, microcephaly, and agenesis of CC. Focal and generalised tonic-clonic seizures were seen from birth. Both individuals died before age 4 years. Seq method: homozygosity mapping, WES. Both affected individuals were homozygous for the SEC31A: c.2776_2777dup, p.Ala927Thrfs*76 variant - not in gnomAD v4.1.1. Functional evidence: Drosophila sec31a -/- null model showed early embryonic lethality. Knockdown of sec31a with RNAi in the eye yielded flies with severe eye phenotypes (disorganised ommatids). Brain-specific knockdown: larvae appeared to develop normally until death in the third instar larvae stage. |
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| Intellectual disability v9.193 | LDB1 |
Arina Puzriakova gene: LDB1 was added gene: LDB1 was added to Intellectual disability. Sources: Literature Q4_25_promote_green tags were added to gene: LDB1. Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LDB1 were set to 39680505; 38091987; 33077954 Phenotypes for gene: LDB1 were set to Congenital hydrocephalus, MONDO:0016349 Review for gene: LDB1 was set to GREEN Added comment: - Allington et al. 2024 (PMID: 39680505) investigate a cohort of 2697 trios with congenital primary cerebral ventriculomegaly using WES. Eight unrelated individuals identified with de novo variants in LDB1 (7 LOF, 1 predicted damaging missense) - exhibiting perinatally diagnosed cerebral ventriculomegaly, including neurosurgically treated congenital hydrocephalus. Additionally, 5/8 GDD, 3/8 autism, 2/8 delayed gross motor development, 2/8 had congenital heart defects (inc. coarctation, PDA), 2/8 camptodactyly. Additional case was identified from GeneMatcher with a de novo frameshift variants in LDB1. Phenotypes include severe ventriculomegaly, absence of well formed gyri, severe limb contractures and camptodactyly. Search of Decipher/DDD also revealed 4 pathogenic de novo variants in LDB1 and associated binding partners in individuals congenital ventriculomegaly. - Torene et al. 2023 (PMID: 38091987) identified three individuals with protein truncating variants. Two individuals with de novo variants both had ventriculomegaly, hypotonia, GDD, craniofacial abnormalities. The third individual inherited the variants from an asymptomatic mother, and displayed developmental delay, hypotonia, congenital heart defects and a small hypoplastic hippocampi but did not have ventriculomegaly or craniofacial anomalies. - Jin et al. 2020 (PMID: 33077954) also report an individual with a de novo LOF variant in this gene who had congenital hydrocephalus but details on this case are otherwise limited. Sources: Literature |
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| Intellectual disability v8.55 | EEFSEC | Achchuthan Shanmugasundram Phenotypes for gene: EEFSEC were changed from neuroseselopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v8.54 | EEFSEC |
Achchuthan Shanmugasundram gene: EEFSEC was added gene: EEFSEC was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: EEFSEC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EEFSEC were set to 39753114 Phenotypes for gene: EEFSEC were set to neuroseselopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 Review for gene: EEFSEC was set to GREEN Added comment: PMID:39753114 reported nine different individuals from eight unrelated families with a selenopathy with early-onset neurodegeneration. Thy were all identified with six different biallelic variants in EEFSEC gene, of which seven families had variants in homozygous state, while one family had variants in compound heterozygous state. They presented with global developmental delay, moderate or severe cognitive impairment, progressive spasticity, ataxia, and seizures. In addition, cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy. This gene has not yet been associated with any relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature |
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| Intellectual disability v3.421 | UROS |
Arina Puzriakova Source Expert Review Red was added to UROS. Rating Changed from Amber List (moderate evidence) to Red List (low evidence) |
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| Intellectual disability v3.254 | UROS | Arina Puzriakova commented on gene: UROS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.3 | RPGRIP1 | Zornitza Stark reviewed gene: RPGRIP1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cone-rod dystrophy 13, MIM# 608194, Leber congenital amaurosis 6, MIM# 613826; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.3 | RPE65 | Zornitza Stark reviewed gene: RPE65: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber congenital amaurosis 2, MIM# 204100, Retinitis pigmentosa 20, MIM# 613794, Retinitis pigmentosa 87 with choroidal involvement, MIM# 618697; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.3 | NMNAT1 | Zornitza Stark reviewed gene: NMNAT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Leber congenital amaurosis 9, MIM# 608553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.3 | UROS | Zornitza Stark reviewed gene: UROS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria, congenital erythropoietic, MIM# 263700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | UROS | BRIDGE consortium edited their review of UROS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | UROS | Louise Daugherty classified UROS as amber | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | UROS | Louise Daugherty commented on UROS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | UROS | BRIDGE consortium reviewed UROS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||