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Mendeliome v2.326 GAK Lucy Spencer gene: GAK was added
gene: GAK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GAK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GAK were set to 37056996
Phenotypes for gene: GAK were set to neurodevelopmental disorder MONDO:0700092, GAK-related
Review for gene: GAK was set to AMBER
Added comment: PMID 37056996 performed a systematic survey of de novo variants in genes encoding phosphatase catalytic subunits in rare disease patients in the 100000 genomes project. Table 2 lists says 3 missense were identified in GAK in individuals with developmental delay or macrocephaly however no variant information is provided. The supplemental data for this paper lists 5 missense variants in GAK, it is unclear which if any of these were observed in the above individuals. only 2 of these variants are absent from gnomad, the rest have over 10 hets each. The paper also mentions one de novo frameshift variant in GAK in DECIPHER in an individual with abnormality of the nervous an musculoskeletal systems. DECIPHER also had an addition de novo missense in an individual with a similar phenotype.
Sources: Literature
Mendeliome v2.319 RIPPLY3 Rylee Peters Marked gene: RIPPLY3 as ready
Mendeliome v2.319 RIPPLY3 Rylee Peters Gene: ripply3 has been classified as Amber List (Moderate Evidence).
Mendeliome v2.319 RIPPLY3 Rylee Peters Classified gene: RIPPLY3 as Amber List (moderate evidence)
Mendeliome v2.319 RIPPLY3 Rylee Peters Gene: ripply3 has been classified as Amber List (Moderate Evidence).
Mendeliome v2.318 RIPPLY3 Rylee Peters gene: RIPPLY3 was added
gene: RIPPLY3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RIPPLY3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RIPPLY3 were set to 30241482; 21177346
Phenotypes for gene: RIPPLY3 were set to Congenital heart disease, MONDO:0005453, RIPPLY3-related
Review for gene: RIPPLY3 was set to AMBER
Added comment: RIPPLY3 encodes a transcriptional corepressor that interacts with TBX1 to modulate cardiac outflow tract development.

PMID: 30241482 reports four individuals from four unrelated families with heterozygous missense RIPPLY3 variants presenting with conotruncal heart defects; these missense variants have 1-20hets in gnomAD v4. Luciferase reporter and co‑immunoprecipitation assays demonstrate reduced TBX1 repression. An earlier study demonstrated that Ripply3-deficient mice exhibit abnormal development of pharyngeal derivatives, including ectopic formation of the thymus and the parathyroid gland, as well as cardiovascular malformation (PMID: 21177346).
Sources: Literature
Mendeliome v2.312 PPL chirag patel Marked gene: PPL as ready
Mendeliome v2.312 PPL chirag patel Gene: ppl has been classified as Green List (High Evidence).
Mendeliome v2.312 PPL chirag patel Classified gene: PPL as Green List (high evidence)
Mendeliome v2.312 PPL chirag patel Gene: ppl has been classified as Green List (High Evidence).
Mendeliome v2.311 PPL chirag patel gene: PPL was added
gene: PPL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPL were set to 34815391
Phenotypes for gene: PPL were set to Eosinophilic esophagitis, MONDO:0005361
Review for gene: PPL was set to GREEN
Added comment: PMID 34815391 reports 17 affected individuals from 7 families with eosinophilic oesophagitis and 6 different heterozygous missense PPL variants. Most variants are rare but 2 are seen in 140 hets (p.Val1377Glu) and 159 hets (p.Glu632Lys) in gnomAD v4. The variants segregated with affected siblings/relatives in 6/7 families, and parental testing was only done in 2/7 families with reduced penetrance noted in those families. One large family also had a DSP (desmoplakin variant segregating with disease). Periplakin (PPL) is a member of the plakin protein family that localize to desmosomes and is highly expressed in the esophagus. PPL knockout EPC2 cells (human esophageal cell lines) demonstrated acantholysis and significantly decreased barrier function. EPC2 cells transduced with PPL variants showed impaired epithelial barrier integrity and reduced barrier function. A wound healing assay showed mutant PPL increased wound‑healing speed, reduced active RhoA, and increased susceptibility to CAPN14‑mediated degradation.
Sources: Literature
Mendeliome v2.176 SORBS2 Lucy Spencer gene: SORBS2 was added
gene: SORBS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SORBS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SORBS2 were set to 34099102; 32808564; 39912518; 31790498
Phenotypes for gene: SORBS2 were set to congenital heart disease MONDO:0005453, SORBS2-related; familial Alzheimer disease MONDO:0100087, SORBS2-related
Review for gene: SORBS2 was set to AMBER
Added comment: PMID 34099102 reports that rare SORBS2 variants are enriched in a cohort of 300 CHD patients. In the supplementary data they report 11 variants in 21 individuals all missense and all present in gnomad most with over 10 hets 1 with 1 hom and 300 hets. Several of the patients had multiple variants of interest in multiple genes. Some functional evidence suggested a few of the missense variants causes protein aggregation. Amber for now

PMID 32808564 identified 2 patients with arrhythmogenic cardiomyopathy and SORBS2 canonical splice variants. Also did some mouse model studies.

PMID: 39912518 5 affected individuals from one family with Alzheimer’s disease and T189M in SORBS2 (T89M in gnomad, 16 hets no homs). Transgenic mice with this variant also showed cognitive decline and increased intraneuronal AB deposition in the cortex.

PMID: 31790498 reports one family with hypotrichosis and woolly hair and a missense in this gene. Not investigated

Amber for all associations
Sources: Literature
Mendeliome v1.4949 MACF1 Lucy Spencer changed review comment from: Biallelic neurodevelopmental disorder GREEN:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense in the early NMD-escape region. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants. Almost all of the missense are rare in gnomad however one p.Leu1349Met has over 1000 hets and 2 homs.

Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant

Monoallelic neurodevelopmental disorder GREEN:
There is a currently well established AD association with Lissencephaly 9 with complex brainstem malformation (MIM#618325) shown to have a GOF mechanism. 2 recent papers PMID: 40925378 Dekker J 2025 and PMID: 41629993 Xi J 2026 have recently reported at least 6 de novo NMD variants in individuals with a nonspecific neurodevelopmental disorder, including developmental delay/I in all and and epilepsy or macro/microcephaly in some. All variants are absent from gnomad. The pLI for this gene is 1 but there are quite a few NMD variants in gnomad with high het counts- however these cluster in exons 36-41 and exon 4 which are only coding in the MANE transcripts and not in other refseq transcripts or highly expressed transcripts in Gtex.

The overlapping phenotype of the mono and biallelic neurodevelopmental disorders may be due to hypomorphic variants causing the biallelic disease, or there may be a correlation to do with the different isoforms of this gene or the location of the variants within the protein. Still a bit of uncertainty around these phenotypes due to the non-specific and variable phenotypes and limited functional validation but enough reports to call them green at this stage

Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.; to: Biallelic neurodevelopmental disorder GREEN:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense in the early NMD-escape region. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants. Almost all of the missense are rare in gnomad however one p.Leu1349Met has over 1000 hets and 2 homs.

Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant

Monoallelic neurodevelopmental disorder GREEN:
There is a currently well established AD association with Lissencephaly 9 with complex brainstem malformation (MIM#618325) shown to have a GOF mechanism. 2 recent papers PMID: 40925378 Dekker J 2025 and PMID: 41629993 Xi J 2026 have recently reported at least 6 de novo NMD variants in individuals with a nonspecific neurodevelopmental disorder, including developmental delay in all and epilepsy or macro/microcephaly in some. All variants are absent from gnomad. The pLI for this gene is 1 but there are quite a few NMD variants in gnomad with high het counts- however these cluster in exons 36-41 and exon 4 which are only coding in the MANE transcripts and not in other refseq transcripts or highly expressed transcripts in Gtex.

The overlapping phenotype of the mono and biallelic neurodevelopmental disorders may be due to hypomorphic variants causing the biallelic disease, or there may be a correlation to do with the different isoforms of this gene or the location of the variants within the protein. Still a bit of uncertainty around these phenotypes due to the non-specific and variable phenotypes and limited functional validation but enough reports to call them green at this stage

Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.
Mendeliome v1.4946 MACF1 Lucy Spencer changed review comment from: Biallelic neurodevelopmental disorder GREEN:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense in the early NMD-escape region. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants. Almost all of the missense are rare in gnomad however one p.Leu1349Met has over 1000 hets and 2 homs.

Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant

Monoallelic neurodevelopmental disorder GREEN:
There is a currently well established AD association with Lissencephaly 9 with complex brainstem malformation (MIM#618325) shown to have a GOF mechanism. 2 recent papers PMID: 40925378 Dekker J 2025 and PMID: 41629993 Xi J 2026 have recently reported at least 6 de novo NMD variants in individuals with a nonspecific neurodevelopmental disorder, all are absent from gnomad. The pLI for this gene is 1 but there are quite a few NMD variants in gnomad with high het counts- however these cluster in exons 36-41 and exon 4 which are only coding in the MANE transcripts and not in other refseq transcripts or highly expressed transcripts in Gtex.

The overlapping phenotype of the mono and biallelic neurodevelopmental disorders may be due to hypomorphic variants causing the biallelic disease, or there may be a correlation to do with the different isoforms of this gene or the location of the variants within the protein. Still a bit of uncertainty around these phenotypes due to the non-specific and variable phenotypes but enough reports to call them green at this stage

Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.; to: Biallelic neurodevelopmental disorder GREEN:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense in the early NMD-escape region. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants. Almost all of the missense are rare in gnomad however one p.Leu1349Met has over 1000 hets and 2 homs.

Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant

Monoallelic neurodevelopmental disorder GREEN:
There is a currently well established AD association with Lissencephaly 9 with complex brainstem malformation (MIM#618325) shown to have a GOF mechanism. 2 recent papers PMID: 40925378 Dekker J 2025 and PMID: 41629993 Xi J 2026 have recently reported at least 6 de novo NMD variants in individuals with a nonspecific neurodevelopmental disorder, including developmental delay/I in all and and epilepsy or macro/microcephaly in some. All variants are absent from gnomad. The pLI for this gene is 1 but there are quite a few NMD variants in gnomad with high het counts- however these cluster in exons 36-41 and exon 4 which are only coding in the MANE transcripts and not in other refseq transcripts or highly expressed transcripts in Gtex.

The overlapping phenotype of the mono and biallelic neurodevelopmental disorders may be due to hypomorphic variants causing the biallelic disease, or there may be a correlation to do with the different isoforms of this gene or the location of the variants within the protein. Still a bit of uncertainty around these phenotypes due to the non-specific and variable phenotypes and limited functional validation but enough reports to call them green at this stage

Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.
Mendeliome v1.4946 MACF1 Lucy Spencer changed review comment from: Biallelic disease

Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.

Neurodevelopmental disorder GREEN/AMBER:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants. Almost all of the missense are rare in gnomad however one p.Leu1349Met has over 1000 hets and 2 homs.

Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant

Mostly missense reported with no functional, not a specific or very consistent phenotype.

Monoallelic:
There is a currently well established AD association with Lissencephaly 9 with complex brainstem malformation (MIM#618325) shown to have a GOF mechanism. But 2 recent papers PMID: 40925378 Dekker J 2025 and PMID: 41629993 Xi J 2026 have recently reported at least 6 de novo NMD variants in individuals with a nonspecific neurodevelopmental disorder. The pLI for this gene is 1 but there are quite a few NMD variants in gnomad with high het counts- however these cluster in exons 36-41 and exon 4 which are only coding in the MANE transcripts and not in other refseq transcripts or highly expressed transcripts in Gtex. ; to: Biallelic neurodevelopmental disorder GREEN:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense in the early NMD-escape region. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants. Almost all of the missense are rare in gnomad however one p.Leu1349Met has over 1000 hets and 2 homs.

Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant

Monoallelic neurodevelopmental disorder GREEN:
There is a currently well established AD association with Lissencephaly 9 with complex brainstem malformation (MIM#618325) shown to have a GOF mechanism. 2 recent papers PMID: 40925378 Dekker J 2025 and PMID: 41629993 Xi J 2026 have recently reported at least 6 de novo NMD variants in individuals with a nonspecific neurodevelopmental disorder, all are absent from gnomad. The pLI for this gene is 1 but there are quite a few NMD variants in gnomad with high het counts- however these cluster in exons 36-41 and exon 4 which are only coding in the MANE transcripts and not in other refseq transcripts or highly expressed transcripts in Gtex.

The overlapping phenotype of the mono and biallelic neurodevelopmental disorders may be due to hypomorphic variants causing the biallelic disease, or there may be a correlation to do with the different isoforms of this gene or the location of the variants within the protein. Still a bit of uncertainty around these phenotypes due to the non-specific and variable phenotypes but enough reports to call them green at this stage

Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.
Mendeliome v1.4935 MACF1 Lucy Spencer changed review comment from: Biallelic disease

Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.

Neurodevelopmental disorder GREEN:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants. Almost all of the missense are rare in gnomad however one p.Leu1349Met has over 1000 hets and 2 homs.

Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant; to: Biallelic disease

Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.

Neurodevelopmental disorder GREEN/AMBER:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants. Almost all of the missense are rare in gnomad however one p.Leu1349Met has over 1000 hets and 2 homs.

Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant

Mostly missense reported with no functional, not a specific or very consistent phenotype.

Monoallelic:
There is a currently well established AD association with Lissencephaly 9 with complex brainstem malformation (MIM#618325) shown to have a GOF mechanism. But 2 recent papers PMID: 40925378 Dekker J 2025 and PMID: 41629993 Xi J 2026 have recently reported at least 6 de novo NMD variants in individuals with a nonspecific neurodevelopmental disorder. The pLI for this gene is 1 but there are quite a few NMD variants in gnomad with high het counts- however these cluster in exons 36-41 and exon 4 which are only coding in the MANE transcripts and not in other refseq transcripts or highly expressed transcripts in Gtex.
Mendeliome v1.4913 CECR2 Lucy Spencer gene: CECR2 was added
gene: CECR2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CECR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CECR2 were set to 41964217; 37424722
Phenotypes for gene: CECR2 were set to Neurodevelopmental disorder, MONDO:0700092, CECR2-related; neural tube defects, susceptibility to MONDO:0020705, CECR2-related
Review for gene: CECR2 was set to GREEN
Added comment: PMID 41964217 reports six individuals from six unrelated families with heterozygous nonsense, frameshift or missense CECR2 variants causing a neurodevelopmental disorder characterized by developmental and speech delay, growth restriction, microcephaly/small head circumference, intellectual disability and variable congenital anomalies. Other common features included gastrointestinal dysmotility, abnormal brain morphology, cardiac anomalies, ophthalmologic anomalies, and seizures/epilepsy in 3 patients. Two variants were confirmed de novo (1 missense 1 nonsense), inheritance information was no available for the other 4. All variant were either absent from gnomad v4 or had only 1 het. all missense were towards the end of the protein p.1385-1428.

PMID 37424722 9 CECR2 variants in 12 patients with neural tube defects. All variants were missense from p. 327-1023 and 5 of them had over 11 hets in gnomad. Phenotypes included anencephaly, hydrocephalus, spina bifida, atelectasis, visceral congestion and more. The paper mentions a mouse model has previous shown LOF of CECR2 results in NTDs and that high homocysteine levels could further reduce CECR2 expression. Functional analysis on 4 missense in this cohort showed reduced CECR2 protein expression on western blot for 3, exposure to homocysteine thiolactone further reduced this expression in increase apoptosis activity while folic acid supplementation counteracted CECR2 expression decline and reduced apoptosis. No inheritance information was available for these variants.

Green for the neurodevelopmental disorder, amber/red for neural tube defects similar to other genes with this association ie VANGL2.
Sources: Literature
Mendeliome v1.4902 MACF1 Lucy Spencer changed review comment from: Biallelic disease

Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.

Neurodevelopmental disorder GREEN:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants.

Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant; to: Biallelic disease

Myasthenic syndrome AMBER:
PMID: 30842214 Oury 2019 1 patient with myasthenic syndrome (ptosis, weakness of extraocular muscles and neck flexors and difficulty swallowing, onset in childhood chet missense p.Leu2208Phe p.Thr1799Ala (in MANE select Leu3768Phe Thr3359Ala). A 2nd patient with mild adult onset limb girdle myasthenic syndrome, homozygous for p.Val1563Met (in MANE select: Val3123Met) also reported in PMID: 37721175 Polavarapu 2024.

Neurodevelopmental disorder GREEN:
PMID: 40925378; Dekker 2025- biallelic patients with a neurodevelopmental disorder. 9 unrelated patients across the main paper and supplementary data, all but 1 have homozygous or compound heterozygous missense spread across the gene, 1 has a homozygous nonsense. All have some degree of ID or developmental delay with variable additional features including microcephaly, hypotonia, muscle weakness, ataxia, or hypomyelination. The majority of their variants are in the plankin domain which is very large p.583-1533, however this is a mix of both recessive and dominant variants. Almost all of the missense are rare in gnomad however one p.Leu1349Met has over 1000 hets and 2 homs.

Also in this papers supplementary data is a review of other biallelic cases in the literature. all but 1 have compound het missense scattered across the gene
PMID: 24476948 1 with fetal akinesia
PMID: 32010038 1 with spastic tetraplegia, dystonia, joint contracture, feeding difficulty and dev delay
PMID: 33600046 3 patients; proximal and distal limb atrophy and weakness in one, axonal polyneuropathy with exotropia in another, and infantile muscular atrophy and weakness in the 3rd.
PMID: 29667327 1 with West syndrome
PMID: 297066461 with corpus callosum hypoplasia. this individual has a chet missense and NMD variant
Mendeliome v1.4744 SPPL2A Lucy Spencer Phenotypes for gene: SPPL2A were changed from Immunodeficiency 86, MIM#619549; Susceptibility to mycobacteria and Salmonella to Immunodeficiency 86, mycobacteriosis MIM#619549
Mendeliome v1.4743 SPPL2A Lucy Spencer Publications for gene: SPPL2A were set to 30127434
Mendeliome v1.4742 SPPL2A Lucy Spencer Classified gene: SPPL2A as Green List (high evidence)
Mendeliome v1.4742 SPPL2A Lucy Spencer Gene: sppl2a has been classified as Green List (High Evidence).
Mendeliome v1.4741 SPPL2A Lucy Spencer reviewed gene: SPPL2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 30127434, 37931111, 39586751; Phenotypes: Immunodeficiency 86, mycobacteriosis MIM#619549; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.4691 APPL1 Sangavi Sivagnanasundram Tag refuted tag was added to gene: APPL1.
Mendeliome v1.4691 APPL1 Sangavi Sivagnanasundram reviewed gene: APPL1: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004159; Phenotypes: monogenic diabetes MONDO:0015967; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.4295 PTPRF Bryony Thompson gene: PTPRF was added
gene: PTPRF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPRF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPRF were set to 24781087
Phenotypes for gene: PTPRF were set to breasts and/or nipples, aplasia or hypoplasia of, 2 MONDO:0014450
Review for gene: PTPRF was set to RED
Added comment: A single consanguineous family with a homozygous variant
Sources: Literature
Mendeliome v1.4215 APPL1 Zornitza Stark Publications for gene: APPL1 were set to 26073777; 36208030
Mendeliome v1.4214 APPL1 Zornitza Stark reviewed gene: APPL1: Rating: RED; Mode of pathogenicity: None; Publications: 40779032; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.4148 SRP72 Lucy Spencer changed review comment from: PMID: 41142505 15yo with thrombocytopenia, mild anemia with macrocytosis and mild leukopenia. found to have a paternally inherited missense in SRP72 (2 hets in gnomad) along with maternally inherited missense (absent from gnomad) in TINF2 and deep intronic variant in TERT (absent from gnomad).

PMID: 41472573 6yo boy with aplastic anemia, pancytopenia and leukopenia, thrombocytopenia and reduced red cell count. Found to have a de novo canonical splice variant c.1502+1G>A that has 63 hets in gnomad. RT-PCR showed retention of 2bp leading to an out of frame product.

PMID: 40510848 1 individual in a congenital neuropenia cohort with an SPR72 variant. Variant only listed in the supplementary material Trp474*, inheritance unknown, absent from gnomad

PMID: 37176611 4yo girl with repeated infections and severe neutropenia. Found to have a paternally inherited balanced translocation t(3;8)(p26;q21)c, as well as maternally inherited synonymous variant in SRP72 and missense in ANKRD26. The synonymous variant in this case has over 4000 homs in gnomad and is very unlikely to be contributing to the phenotype.

Only 1 compelling report in PMID: 40510848, however other NMD variants are present in gnomad with high het counts. borderline amber/green; to: PMID: 41142505 15yo with thrombocytopenia, mild anemia with macrocytosis and mild leukopenia. found to have a paternally inherited missense in SRP72 (2 hets in gnomad) along with maternally inherited missense (absent from gnomad) in TINF2 and deep intronic variant in TERT (absent from gnomad).

PMID: 41472573 6yo boy with aplastic anemia, pancytopenia and leukopenia, thrombocytopenia and reduced red cell count. Found to have a de novo canonical splice variant c.1502+1G>A that has 63 hets in gnomad. RT-PCR showed retention of 2bp leading to an out of frame product.

PMID: 40510848 1 individual in a congenital neuropenia cohort with an SPR72 variant. Variant only listed in the supplementary material Trp474*, inheritance unknown, absent from gnomad

PMID: 37176611 4yo girl with repeated infections and severe neutropenia. Found to have a paternally inherited balanced translocation t(3;8)(p26;q21)c, as well as maternally inherited synonymous variant in SRP72 and missense in ANKRD26. The synonymous variant in this case has over 4000 homs in gnomad and is very unlikely to be contributing to the phenotype.

Only 1 compelling report in PMID: 40510848, however other NMD variants are present in gnomad with high het counts. borderline amber/green
Mendeliome v1.4146 SRP72 Lucy Spencer edited their review of gene: SRP72: Added comment: PMID: 41142505 15yo with thrombocytopenia, mild anemia with macrocytosis and mild leukopenia. found to have a paternally inherited missense in SRP72 (2 hets in gnomad) along with maternally inherited missense (absent from gnomad) in TINF2 and deep intronic variant in TERT (absent from gnomad).

PMID: 41472573 6yo boy with aplastic anemia, pancytopenia and leukopenia, thrombocytopenia and reduced red cell count. Found to have a de novo canonical splice variant c.1502+1G>A that has 63 hets in gnomad. RT-PCR showed retention of 2bp leading to an out of frame product.

PMID: 40510848 1 individual in a congenital neuropenia cohort with an SPR72 variant. Variant only listed in the supplementary material Trp474*, inheritance unknown, absent from gnomad

PMID: 37176611 4yo girl with repeated infections and severe neutropenia. Found to have a paternally inherited balanced translocation t(3;8)(p26;q21)c, as well as maternally inherited synonymous variant in SRP72 and missense in ANKRD26. The synonymous variant in this case has over 4000 homs in gnomad and is very unlikely to be contributing to the phenotype.

Only 1 compelling report in PMID: 40510848, however other NMD variants are present in gnomad with high het counts. borderline amber/green; Changed publications: 40922878, 3717661, 41472573, 40510848, 41142505
Mendeliome v1.3747 KCTD1 Zornitza Stark Phenotypes for gene: KCTD1 were changed from Scalp-ear-nipple syndrome MIM#181270 to Scalp-ear-nipple syndrome MIM#181270; Dental radicular dysplasia, MIM# 621434
Mendeliome v1.3479 EIPR1 Thomas Cloney gene: EIPR1 was added
gene: EIPR1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EIPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIPR1 were set to 41058046
Phenotypes for gene: EIPR1 were set to Mendelian neurodevelopmental disorder MONDO:0100500, EIPR1-related
Penetrance for gene: EIPR1 were set to unknown
Review for gene: EIPR1 was set to GREEN
Added comment: Report of 8 individuals from 6 unrelated consanguinous families with homozygous EIPR1 variants (5 different variants).
Phenotype: All had global developmental delay (range of severity), with significant motor delay (5/8 never attained walking). Neurological manifestations: 2/8 Hypotonia, 4/8 had spasticity. 5/8 had microcepahly. MRI Brain abnormalities included: delayed myelination, hypoplasia of the corpus callosum, mild cerebellar atrophy, dysmorphic lateral ventricles. (Limited phenotypic information in pre-print - all in supplementary data)
Functional data: In vitro functional work show reduced protrien levels and interaction with EARP and GARP; and in vivo zebrafish models with knowckout of EIPR1 result in neurodevelopmental and locomotor defects
Sources: Literature
Mendeliome v1.3301 CPD Sarah Milton changed review comment from: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.
All families consanguineous.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature; to: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to assist in function of the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.
All families consanguineous.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature
Mendeliome v1.3289 BBOX1 Zornitza Stark gene: BBOX1 was added
gene: BBOX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BBOX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BBOX1 were set to 41022783
Phenotypes for gene: BBOX1 were set to Carnitine deficiency, MONDO:0017716, BBOX1-related
Review for gene: BBOX1 was set to AMBER
Added comment: Three individuals from two unrelated families reported, presenting with myopathy, neurodevelopmental delay, and later-onset psychiatric manifestations. C. elegans knockout and patient-variant models show embryonic lethality rescued by L‑carnitine supplementation
Sources: Literature
Mendeliome v1.3288 CPD Sarah Milton changed review comment from: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature; to: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.
All families consanguineous.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature
Mendeliome v1.3288 CPD Sarah Milton gene: CPD was added
gene: CPD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CPD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CPD were set to PMID: 41026541
Phenotypes for gene: CPD were set to Nonsyndromic genetic hearing loss, MONDO:0019497, CPD-related
Review for gene: CPD was set to GREEN
Added comment: CPD encodes carboxypeptidase D which is part of the metallocarboxylpeptidases family. These enzymes are zinc dependent and cleave c terminal arginine and lysine. Which in turn has a role in production of nitric oxide which is known to play role in the cochlea.

PMID: 41026541 describes 5 individuals from 3 families with biallelic missense variants in CPD who have prelingual onset bilateral profound SNHL. No syndromic features were noted in affected probands.
All variants appropriately rare in gnomad v4 for a rare recessive disorder.
No homozygous loss of function variants in gene in gnomad v4.

Functional studies demonstrated reduction in nitric oxide levels in patient cells as well as increased apoptosis with rescue upon introduction on L arginine. Proposed mechanism of disease is loss of function.
Drosophila studies demonstrated disrupted Johnston’s organ morphology and impaired auditory transduction with partial rescue by arginine. Other supportive functional models discussed in paper.

Authors suggest potential treatment of affected individuals with arginine supplementation.
Sources: Literature
Mendeliome v1.2271 DMRT1 Zornitza Stark edited their review of gene: DMRT1: Added comment: DMRT1 gene exclusively expressed in male gonads. Thought not to affect ovarian development.
Gene included three international studies - see PMID: 28295047 supplemental article Fig 1 patient 19, 46XY with hypoplastic labia, uterus present had DMRT1 c.251A>G p.Tyr84Cys maternally inherited VOUS
PMID: 26005864: p.R111G also described in complete gonadal dysgenesis; Changed rating: AMBER; Changed publications: 31479588, 24934491, 29527098, 26005864, 28295047; Changed phenotypes: 46,XY disorder of sex development, MONDO:0020040
Mendeliome v1.1568 APPL1 Bryony Thompson Publications for gene: APPL1 were set to 26073777
Mendeliome v1.1567 APPL1 Bryony Thompson Classified gene: APPL1 as Red List (low evidence)
Mendeliome v1.1567 APPL1 Bryony Thompson Gene: appl1 has been classified as Red List (Low Evidence).
Mendeliome v1.1566 APPL1 Bryony Thompson edited their review of gene: APPL1: Added comment: PMID: 36208030 - a study using the UK Biobank comparing individuals with and without diabetes found LoF variants in APPL1 were ‘Inconsistent’ with being high penetrant for diabetes (failed both statistical criteria - enrichment & comparison to maximum credible allele frequency). Refutes previous study.; Changed rating: RED; Changed publications: 26073777, 36208030
Mendeliome v1.1296 IRF4 Zornitza Stark Phenotypes for gene: IRF4 were changed from Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724; Combined immunodeficiency to Combined immunodeficiency, MONDO:0015131, IRF4-related
Mendeliome v1.697 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Mendeliome v1.601 TRPC5 Hazel Phillimore gene: TRPC5 was added
gene: TRPC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890
Phenotypes for gene: TRPC5 were set to Intellectual disability; autistic spectrum disorder
Review for gene: TRPC5 was set to AMBER
Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570:
Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents.
Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened).
(This variant is absent in gnomAD v2.1.1).

Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted.

Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include:
PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested).

In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*).
NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1).

However, looking further into the three references, the evidence is not as clear or as accurate as was stated.

The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929).

Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned.

Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2).
Sources: Literature
Mendeliome v1.346 COQ4 Zornitza Stark changed review comment from: Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. IUGR reported. At least 9 unrelated families reported.; to: Primary coenzyme Q10 deficiency-7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth. IUGR reported. At least 9 unrelated families reported.

Treatment: CoQ10 supplementation can limit disease progression and reverse some clinical manifestations.
Mendeliome v1.206 C18orf32 Naomi Baker gene: C18orf32 was added
gene: C18orf32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: C18orf32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C18orf32 were set to PMID:35107634
Phenotypes for gene: C18orf32 were set to Neurodevelopmental disorder (MONDO:0700092), C18orf32-related
Review for gene: C18orf32 was set to RED
Added comment: Two siblings reported as affected, although sequencing only performed in one sibling, with homozygous loss-of-function variant identified. Clinical presentation included developmental delay, recurrent lower respiratory tract infections, sparse rough hair, roving eye movements, hypotonia, bilateral ankle contractures and inverted nipples.
Sources: Literature
Mendeliome v0.14239 RIPPLY2 Zornitza Stark Marked gene: RIPPLY2 as ready
Mendeliome v0.14239 RIPPLY2 Zornitza Stark Gene: ripply2 has been classified as Green List (High Evidence).
Mendeliome v0.14239 RIPPLY2 Zornitza Stark Phenotypes for gene: RIPPLY2 were changed from to Spondylocostal dysostosis 6, MIM# 616566
Mendeliome v0.14238 RIPPLY2 Zornitza Stark Publications for gene: RIPPLY2 were set to
Mendeliome v0.14237 RIPPLY2 Zornitza Stark Mode of inheritance for gene: RIPPLY2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.14236 RIPPLY2 Zornitza Stark edited their review of gene: RIPPLY2: Changed rating: GREEN
Mendeliome v0.14236 RIPPLY2 Zornitza Stark reviewed gene: RIPPLY2: Rating: ; Mode of pathogenicity: None; Publications: 25343988, 33410135, 32212228, 29761784; Phenotypes: Spondylocostal dysostosis 6, MIM# 616566; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.13885 APPL1 Elena Savva Phenotypes for gene: APPL1 were changed from Maturity-onset diabetes of the young, type 14 MIM#616511 to Maturity-onset diabetes of the young, type 14 MIM#616511
Mendeliome v0.13885 APPL1 Elena Savva Phenotypes for gene: APPL1 were changed from Maturity-onset diabetes of the young, type 14 MIM#616511 to Maturity-onset diabetes of the young, type 14 MIM#616511
Mendeliome v0.13881 APPL1 Elena Savva Mode of inheritance for gene: APPL1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13881 APPL1 Elena Savva Classified gene: APPL1 as Amber List (moderate evidence)
Mendeliome v0.13881 APPL1 Elena Savva Gene: appl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.13880 APPL1 Elena Savva Phenotypes for gene: APPL1 were changed from to Maturity-onset diabetes of the young, type 14 MIM#616511
Mendeliome v0.13880 APPL1 Elena Savva Publications for gene: APPL1 were set to
Mendeliome v0.13880 APPL1 Elena Savva Mode of inheritance for gene: APPL1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v0.13880 APPL1 Elena Savva Classified gene: APPL1 as Amber List (moderate evidence)
Mendeliome v0.13880 APPL1 Elena Savva Gene: appl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v0.13879 APPL1 Elena Savva Marked gene: APPL1 as ready
Mendeliome v0.13879 APPL1 Elena Savva Gene: appl1 has been classified as Green List (High Evidence).
Mendeliome v0.12546 CAV3 Ain Roesley Phenotypes for gene: CAV3 were changed from to Myopathy, distal, Tateyama type MIM#614321; Rippling muscle disease 2 MIM#606072; Creatine phosphokinase, elevated serum MIM#123320
Mendeliome v0.12544 CAV3 Ain Roesley reviewed gene: CAV3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32004987, 28807458, 27312022, 10746614; Phenotypes: Myopathy, distal, Tateyama type MIM#614321, Rippling muscle disease 2 MIM#606072, Creatine phosphokinase, elevated serum MIM#123320; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.11071 CHKA Konstantinos Varvagiannis gene: CHKA was added
gene: CHKA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHKA were set to 35202461
Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature
Penetrance for gene: CHKA were set to Complete
Review for gene: CHKA was set to GREEN
Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants.

Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6.

Eventual previous genetic testing was not discussed.

Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies.

Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype.

3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2):
- c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families],
- c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents],
- c.2T>C/p.(Met1?) [1 hmz individual born to related parents],
- c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual.

CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes.

CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP.

As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants].

Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc.

CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect.

In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine).

Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively).

NMD is thought to underly the deleterious effect of the frameshift one (not studied).

The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein.

Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714).

There is no associated phenotype in OMIM, Gene2Phenotype or SysID.

Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset).
Sources: Literature
Mendeliome v0.9832 INPPL1 Zornitza Stark Marked gene: INPPL1 as ready
Mendeliome v0.9832 INPPL1 Zornitza Stark Gene: inppl1 has been classified as Green List (High Evidence).
Mendeliome v0.9832 INPPL1 Zornitza Stark Phenotypes for gene: INPPL1 were changed from to Opsismodysplasia MIM#258480
Mendeliome v0.9831 INPPL1 Zornitza Stark Publications for gene: INPPL1 were set to
Mendeliome v0.9830 INPPL1 Zornitza Stark Mode of inheritance for gene: INPPL1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9829 INPPL1 Zornitza Stark reviewed gene: INPPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9810 KCTD1 Zornitza Stark Phenotypes for gene: KCTD1 were changed from to Scalp-ear-nipple syndrome MIM#181270
Mendeliome v0.9785 INPPL1 Ain Roesley reviewed gene: INPPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23273567, 34529350, 34094554; Phenotypes: Opsismodysplasia MIM#258480; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v0.9779 KCTD1 Ain Roesley reviewed gene: KCTD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23541344, 31324836; Phenotypes: Scalp-ear-nipple syndrome MIM#181270; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v0.9348 SPPL2A Zornitza Stark Phenotypes for gene: SPPL2A were changed from Susceptibility to mycobacteria and Salmonella to Immunodeficiency 86, MIM#619549; Susceptibility to mycobacteria and Salmonella
Mendeliome v0.9347 SPPL2A Zornitza Stark edited their review of gene: SPPL2A: Changed phenotypes: Immunodeficiency 86, MIM#619549, Susceptibility to mycobacteria and Salmonella
Mendeliome v0.8807 VPS50 Zornitza Stark gene: VPS50 was added
gene: VPS50 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS50 were set to 34037727
Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum
Review for gene: VPS50 was set to AMBER
Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging.

Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)).

VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor.

As discussed by Schneeberger et al (refs provided in text):
- VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development.
- Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality.

Studies performed by Schneeberger et al included:
- Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del).
- Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels.
- Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts.
- Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function.

As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders".

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.
Sources: Literature
Mendeliome v0.8741 TCF7L2 Zornitza Stark changed review comment from: 2 reviews
Konstantinos Varvagiannis (Other)
I don't know

Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants.

Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11).

One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury.

TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts.

Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development.

Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1].

The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA).

No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism.

There are no variant or other studies performed, nor any animal models discussed.

In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs).

Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm.

There is no other associated phenotype (notably NDD) in OMIM.
G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF).
SysID includes this gene within the autism candidate genes and current primary ID genes.; to: Dias et al (2021 - PMID: 34003604) describe the phenotype of 11 unrelated individuals harboring de novo missense/truncating TCF7L2 variants.

Features included DD in childhood (motor delay in 8/11, speech delay in 11/11), intellectual abilities ranging from average cognitive functioning to mild/moderate ID (the latter observed in 5/11), myopia (6/11) , dysmorphic features, variable orthopedic findings, and neuropsychiatric comorbidities incl. ASD (4/11) / ADHD (4/11).

One additional (12th) individual was excluded from this summary due to concurrent diagnosis of hypoxic-ischemic injury.

TCF7L2 on 10q25 encodes transcription factor 7-like 2, a high mobility group (HMG) box-containing transcription factor. As the authors discuss, the protein mediates canonical Wnt signaling. Secreted Wnt proteins lead to release of beta-catenin (CTNNB1) which after translocation to the nucleus acts with DNA-binding factors incl. TCF7L2 to turn on Wnt-responsive target genes. As a result TCF7L2 acts with beta-catenin as a switch for transcriptional regulation. Multiple alternative spliced TCF7L2 transcripts mediate it's function and specificity of transcriptional repertoire in a variety of tissues and contexts.

Dias et al provide references for its role in nervous system development incl. neurogenesis and thalamic development.

Variants in all cases occurred as de novo events with pLoF (stopgain, frameshift, splicing) ones predicted to lead to NMD. Missense variants occurred in all cases in or adjacent to the HMG box domain [aa 350-417]. 5 different missense variants affecting 3 residues were reported incl. c.1142A>C, c.1143C>G (leading to Asn381Thr/Lys respectively), c.1250G>T (Trp417Leu), c.1267T>C, c.1268A>G (leading to Tyr423His/Cys) [NM_001146274.1].

The gene has a pLI of 0.99-1 gnomAD/ExAC while there is a region of missense constraint encompassing the HMG box domain (the latter is an evolutionary conserved region mediating interactions with DNA).

No phenotypic differences were observed among individuals with pLoF and missense SNVs, and haploinsufficiency is presumed to be the underlying mechanism.

There are no variant or other studies performed, nor any animal models discussed.

In supplementary table 2, the authors provide several references to previous large scale sequencing studies with brief/incomplete descriptions of individuals de novo TCF7L2 variants and neurodevelopmental disorder (ID/ASD - Iossifov, De Rubeis, Lelieveld, McRae/DDD study and many other Refs).

Heterozygous TCF7L2 variants are thought to confer susceptibility to type diabetes mellitus (MIM 125853). Individuals reported by Dias et al did not have endocrine abnormalities including DM. A study by Roychowdhury et al (2021 - PMID: 34265237) suggests that regulatory variants in TCF7L2 are associated with thoracic aneurysm.

There is no other associated phenotype (notably NDD) in OMIM.
G2P includes TCF7L2 in its DD panel (Disease : TC7L2-related DD, Confidence:confirmed, Monoallelic, LoF).
SysID includes this gene within the autism candidate genes and current primary ID genes.
Mendeliome v0.8511 CAMK4 Zornitza Stark gene: CAMK4 was added
gene: CAMK4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350
Phenotypes for gene: CAMK4 were set to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus
Review for gene: CAMK4 was set to GREEN
Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant.

Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms.

CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018).

The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below].

Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function.

Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported.

Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below).

Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function.

Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID.

---

The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy.

Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F

Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one.

Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein.

Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect.

To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV.

Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect.

----

Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20].

----

Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).
Sources: Expert Review
Mendeliome v0.7944 SCN7A Zornitza Stark gene: SCN7A was added
gene: SCN7A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCN7A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCN7A were set to 32732226
Phenotypes for gene: SCN7A were set to Holoprosencephaly
Review for gene: SCN7A was set to RED
Added comment: Novel candidate gene identified in a fetus with holoprosencephaly detected by ultrasound. Autopsy showed multiple congenital abnormalities including IUGR, microcephaly, bilateral, ablepharon, corpus callosum agenesis, myelomeningocele, tracheal atresia, absent nipples, unilateral simian crease, and hypoplastic phalanges. Compound heterozygous variants including a truncating variant were found by exome sequencing with concordant segregation.
Sources: Literature
Mendeliome v0.6505 IRF4 Bryony Thompson Phenotypes for gene: IRF4 were changed from Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724 to Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724; Combined immunodeficiency
Mendeliome v0.6228 SLC46A1 Zornitza Stark changed review comment from: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system. More than 5 unrelated families reported.; to: Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhoea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system. More than 5 unrelated families reported.
Mendeliome v0.5229 PRKAR1B Konstantinos Varvagiannis gene: PRKAR1B was added
gene: PRKAR1B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Penetrance for gene: PRKAR1B were set to unknown
Review for gene: PRKAR1B was set to AMBER
Added comment: Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Mendeliome v0.4743 SCN1A Zornitza Stark edited their review of gene: SCN1A: Added comment: Note we have reported the association with AMC previously in PMID 29543227 (Supplementary info) in an infant presenting with AMC and severe EE, and de novo p.(Ile1347Asn) variant which at the time was thought to only partially explain the phenotype, but in light of this new report, likely fully explains the phenotype. Given the presence of severe seizure disorder in the two infants who were phenotyped in the newborn period, this likely represents the severe end of the spectrum of SCN1A-related disorders rather than a distinct association.; Changed phenotypes: Epileptic encephalopathy, early infantile, 6 (Dravet syndrome), MIM# 607208, Genetic Epilepsy Febrile Seizures plus (GEFS+) Syndrome, Febrile seizures, Arthrogryposis multiplex congenita
Mendeliome v0.4262 KMT2D Zornitza Stark edited their review of gene: KMT2D: Added comment: Four further individuals with KMT2D-associated neurodevelopmental syndrome reported. Features include: athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. Two of the four individuals had severe interstitial lung disease.; Changed publications: 31949313, 32083401
Mendeliome v0.3872 LMBRD2 Zornitza Stark gene: LMBRD2 was added
gene: LMBRD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LMBRD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMBRD2 were set to 32820033; https://doi.org/10.1101/797787
Phenotypes for gene: LMBRD2 were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Abnormality of nervous system morphology; Abnormality of the eye
Mode of pathogenicity for gene: LMBRD2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: LMBRD2 was set to GREEN
Added comment: 13 individuals with dn missense SNVs overall, overlapping features for 10 with available phenotype / a recurring variant has been identified in 2 different studies.

► Malhotra et al (2020 - PMID: 32820033) report on 10 unrelated individuals with de novo missense LMBRD2 variants. Features included DD (9/10), ID (6/8 of relevant age), microcephaly (7/10), seizures (5/10 - >=3 different variants), structural brain abnormalities (e.g. thin CC in 6/9), highly variable ocular abnormalities (5/10) and dysmorphic features in some (7/10 - nonspecific). All had variable prior non-diagnostic genetic tests (CMA, gene panel, mendeliome, karyotype). WES/WGS revealed LMBRD2 missense variants, in all cases de novo. A single individual had additional variants with weaker evidence of pathogenicity. 5 unique missense SNVs and 2 recurrent ones (NM_001007527:c.367T>C - p.Trp123Arg / c.1448G>A - p.Arg483His) were identified. These occurred in different exons. Variants were not present in gnomAD and all had several in silico predictions in favor of a deleterious effect. There was phenotypic variability among individuals with the same variant (e.g. seizures in 1/3 and microchephaly in 2/3 of those harboring R483H). The gene has a pLI of 0 (although o/e ranges from 0.23 to 0.55), %HI of 15.13 and z-score of 2.27. The authors presume that haploinsufficiency may not apply, and consider a gain-of-function/dominant-negative effect more likely. As the authors comment LMBRD2 (LMBR1 domain containing 2) encodes a membrane bound protein with poorly described function. It is widely expressed across tissues with notable expression in human brain (also in Drosophila, or Xenopus laevis). It displays high interspecies conservation. It has been suggested (Paek et al - PMID: 28388415) that LMBRD2 is a potential regulator of β2 adrenoreceptor signalling through involvement in GPCR signalling.

► Kaplanis et al (2020 - https://doi.org/10.1101/797787) in a dataset of 31058 parent-offspring trios (WES) previously identified 3 individuals with developmental disorder, harboring c.1448G>A - p.Arg483His. These individuals (1 from the DDD study, and 2 GeneDx patients) appear in Decipher. [ https://decipher.sanger.ac.uk/ddd/research-variant/40e17c78cc9655a6721006fc1e0c98db/overview ]. The preprint by Kaplanis et al is cited by Malhotra et al, with Arg483His reported in 6 patients overall in both studies.
Sources: Literature
Mendeliome v0.3834 TAF1C Zornitza Stark gene: TAF1C was added
gene: TAF1C was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: TAF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF1C were set to 32779182
Phenotypes for gene: TAF1C were set to Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology
Review for gene: TAF1C was set to AMBER
Added comment: Knuutinen et al (2020 - PMID: 32779182) report on 2 individuals from 2 consanguineous families, homozygous for TAF1C missense variants. Both presented with an early onset neurological phenotype with severe global DD, ID (2/2 - moderate and profound), spasticity (2/2), ophthalmic findings (strabismus 2/2, nystagmus 1/2). Epilepsy, abnormal brain MRI (cerebral and cerebellar atrophy and white matter hyperintensities) as well and additional findings were reported in one (always the same individual). Following a normal CMA, exome in the first case revealed a homozygous missense SNV (NM_005679.3:c.1165C>T / p.Arg389Cys) supported by in silico predictions. mRNA and protein levels were substantially reduced in fibroblasts from this subject. Only the patient and parents were tested for the variant but not 3 unaffected sibs (fig1). The second individual was homozygous for another missense variant (p.Arg405Cys) also supported by in silico predictions. The girl was the single affected person within the family with an unaffected sib and parents heterozygous for the variant. Several other unaffected relatives in the extended pedigree were either carriers for this variant or homozygous for the wt allele. TAF1C encodes the TATA-box binding protein associated factor (TAF) RNA polymerase I subunit. RNA polymerase I (Pol I) transcribes genes to produce rRNA. For Pol I to initiate transcription, two transcription factors are required : UBF (upstream binding factor encoded by UBTF) and SL1 (selectivity factor 1). The latter is formed by TBP (TATA-binding protein) and 3 Pol I-specific TBP-associated factors (TAFs). A recurrent de novo missense variant in UBTF (encoding the other Pol I transcription factor) causes a disorder with highly similar features. The specific variant acts through a gain-of-function mechanism (and not by LoF which appears to apply for TAF1C based on expression data). The authors hypothesize that altered Pol I activity and resulting ribosomal stress could cause the microcephaly and leukodystrophy (both reported in 1 - the same - individual).
Sources: Expert list
Mendeliome v0.3327 KIF21B Zornitza Stark gene: KIF21B was added
gene: KIF21B was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF21B were set to 32415109
Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly
Mode of pathogenicity for gene: KIF21B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KIF21B was set to GREEN
Added comment: Asselin et al (2020 - PMID: 32415109) report on 4 individuals with KIF21B pathogenic variants. DD/ID (borderline intellectual functioning to severe ID) was a feature in all. Variable other findings included brain malformations (CCA) and microcephaly. 3 missense variants and a 4-bp insertion were identified, in 3 cases as de novo events while in a single subject the variant was inherited from the father who was also affected. The authors provide evidence for a role of KIF21B in the regulation of processes involved in cortical development and deleterious effect of the missense variants impeding neuronal migration and kinesin autoinhibition. Phenotypes specific to variants (e.g. CCA or microcephaly) were recapitulated in animal models. Missense variants are thought to exert a gain-of-function effect. As commented on, the 4-bp duplication (/frameshift) variant might not be pathogenic. In blood sample from the respective individual, RT-qPCR analysis suggested that haploinsufficiency (NMD) applies. Although Kif21b haploinsufficiency in mice was shown to lead to impaired neuronal positioning, the gene might partially tolerate LoF variants as also suggested by 28 such variants in gnomAD. Homozygous Kif21b ko mice display severe morphological abnormalities, partial loss of commissural fibers, cognitive deficits and altered synaptic transmission (several refs to previous studies provided by the authors).
Sources: Expert Review
Mendeliome v0.2825 PDXK Russell Gear gene: PDXK was added
gene: PDXK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDXK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDXK were set to (PMID: 31187503)
Phenotypes for gene: PDXK were set to Axonal polyneuropathy; optic atrophy
Review for gene: PDXK was set to RED
Added comment: Currently two unrelated families with axonal polyneuropathy and optic atrophy described in the same paper, with bi-allelic PDXK pathogenic variants. Functional work in the same paper includes work on patient derived fibroblasts, measurement of an axonal damage biomarker (NFL protein), and response to PLP supplementation treatment.

Need one further unrelated family to upgrade to green?
Sources: Literature
Mendeliome v0.2294 IRF4 Zornitza Stark Phenotypes for gene: IRF4 were changed from to Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724
Mendeliome v0.2290 IRF4 Zornitza Stark reviewed gene: IRF4: Rating: RED; Mode of pathogenicity: None; Publications: 29537367; Phenotypes: Whipple's disease, [Skin/hair/eye pigmentation, variation in, 8] 611724; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v0.1965 SPPL2A Zornitza Stark Marked gene: SPPL2A as ready
Mendeliome v0.1965 SPPL2A Zornitza Stark Gene: sppl2a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.1965 SPPL2A Zornitza Stark Classified gene: SPPL2A as Amber List (moderate evidence)
Mendeliome v0.1965 SPPL2A Zornitza Stark Gene: sppl2a has been classified as Amber List (Moderate Evidence).
Mendeliome v0.1964 SPPL2A Zornitza Stark gene: SPPL2A was added
gene: SPPL2A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SPPL2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPPL2A were set to 30127434
Phenotypes for gene: SPPL2A were set to Susceptibility to mycobacteria and Salmonella
Review for gene: SPPL2A was set to AMBER
Added comment: Three individuals from two unrelated consanguineous family with two different homozygous splice site variants, functional data.
Sources: Expert list
Mendeliome v0.1744 SLC25A32 Zornitza Stark gene: SLC25A32 was added
gene: SLC25A32 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC25A32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A32 were set to 26933868; 28443623
Phenotypes for gene: SLC25A32 were set to Exercise intolerance, riboflavin-responsive, MIM# 616839
Review for gene: SLC25A32 was set to GREEN
Added comment: Two unrelated families reported with functional data. Muscle biopsy showed ragged-red fibers and lipid storage mainly in type I oxidative fibers, small type II fibers, and poor immunostaining for succinate dehydrogenase (FAD-dependent mitochondrial respiratory chain complex II). Oral supplementation with riboflavin led to dramatic improvement in the clinical and biologic abnormalities.
Sources: Expert list
Mendeliome v0.0 RIPPLY2 Zornitza Stark gene: RIPPLY2 was added
gene: RIPPLY2 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: RIPPLY2 was set to Unknown
Mendeliome v0.0 INPPL1 Zornitza Stark gene: INPPL1 was added
gene: INPPL1 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: INPPL1 was set to Unknown
Mendeliome v0.0 APPL1 Zornitza Stark gene: APPL1 was added
gene: APPL1 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: APPL1 was set to Unknown