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| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 |
Ida Ertmanska changed review comment from: HURIEZ SYNDROME PMID: 35212137 Loh et al., 2022 Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age. PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 32769257 Alruwaili & Hai, 2019 Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform. PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).; to: HURIEZ SYNDROME PMID: 35212137 Loh et al., 2022 Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age. Family 1 - proband had mild hyperkeratosis of soles, thin palmar skin, and weak, pointed nails. Sanger seq revealed a heterozygous 11-bp deletion in SMARCAD1: g.94253671_94253682del. Family 2 - male proband presented with scleroatrophy of hands, contracture of the little finger, sclerodactyly of distal extremities, hypoplastic nails, hypohidrosis. Proband and his affected mother were both het for a deletion affecting the SMARCAD1 donor splice site: g.94253673del Family 3 - case previously described in PMID: 8731679 Hamm, 1996 and PMID: 29409814 Günther et al., 2018 PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 32769257 Alruwaili & Hai, 2019 Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform. PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026). |
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| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 |
Ida Ertmanska changed review comment from: HURIEZ SYNDROME PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).; to: HURIEZ SYNDROME PMID: 35212137 Loh et al., 2022 Report of 3 Huriez syndrome (HRZ) families from Croatia, the Netherlands, and Germany. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed squamous cell carcinoma at 32 years of age. PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 32769257 Alruwaili & Hai, 2019 Report of a 60yo Saudi Arabian man with isolated adermatoglyphia, het for c.378+1G>T in SMARCAD1 short isoform. PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026). |
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| Ichthyosis and erythrokeratoderma v4.17 | SMARCAD1 |
Ida Ertmanska changed review comment from: HURIEZ SYNDROME PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 2 families with Huriez syndrome. SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1. Variant co-segregated with disease, maximal LOD score was 3.01. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026).; to: HURIEZ SYNDROME PMID: 33400266 Loh et al., 2021 Report of a large pedigree with Huriez syndrome, caused by a large deletion that abrogates the skin‐specific isoform of SMARCAD1 Affected patients had evidence of scleroatrophy of the hands, some with subtle tapering of the fingers. There was ridging and hypoplasia of the nails. There was mild hyperkeratosis of the palms. On the soles of the feet, focal hyperkeratosis was seen. Good segregation evidence: NC_000004.12:g.94252297_94253585del was present in sampled affected individuals (n = 7) and was absent in unaffected individuals (n = 2). PMID: 29409814 Günther et al., 2018 Report of 3 families with Huriez syndrome (congenital palmoplantar keratosis, scleroatrophic changes of the hands and feet, and an increased risk for cutaneous squamous cell carcinoma). SMARCAD1 variants in the skin specific isoform were highlighted : c.378+2T>C in family A, SMARCAD1 c.378+2_3insT in Family B, and c.363_378+2del in family C. BASAN SYNDROME: PMID: 34909722 Elhaji et al., 2021 Report of 2 families (Canadian and Dutch) with Basan syndrome: Dutch family: mother and 2 children affected. Mother presented to dermatology clinic at 39 yrs - examination showed adermatoglyphia, hypohidrosis, tapered fingertips, painful palmoplantar punctate keratoderma and punctate hyperkeratosis. She had transient milia at birth. Onychorrhexis with deep longitudinal ridges and Beau lines were also seen. Her children, aged 7yrs and 10yrs, were similarly affected. In addition, callosities were observed on their palms, wrists, and soles of the feet. No other abnormalities regarding their hair, mouth, or teeth were identified. Variant c.374_378+7del was identified in SMARCAD1 short isoform. Canadian family: total 12 individuals affected, with a clear dominant inheritance pattern. All 12 had adermatoglyphia, multiple transient milia on the face, and suffered from lack of sweat and susceptibility to heat strokes. 4/12 had webbed fingers. Proband twin neonates developed blistering near the ankles at birth that healed within days. Normal nails, hair, teeth, and skin pigmentation in all patients. Complex rearrangement was identified in this family, including a deletion of ~50.9 kb and an inverted duplication of ~23.4 kb. The deletion encompasses exons 1‒9 of SMARCAD1 long isoform and exon 1 of the short isoform and includes the first exon of the long noncoding RNA (LOC101929210). PMID: 30289605 Valentin et al., 2018 Case report of a 10 day old male with bilateral heel erosions, which had been bullae at birth. He developed no further bullae or erosions. He was also noted to have innumerable congenital milia around the face, adermatoglyphia of his finger and toes, onychorrhexis, hyperpigmented macules on the hands and feet, and a waxy keratoderma with fine wrinkling of the palms and soles. No hair or teeth anomalies present. Proaband was het for NM_001254949.1:c.-10 + 2 T > G, in the donor splice site of exon 1 of the skin-specific isoform. PMID: 26932190 Li et al., 2016 Chinese family with Basan syndrome. Some patients presented with hyperpigmentation and knuckle pads in addition to classical symptoms of rapidly healing congenital acral bullae, congenital milia and lack of fingerprints. Hair, eyebrows, eyelashes, teeth and nails were all normal. Hypohidrosis was also noted in all 8 affected individuals. Hyperpigmentation was noted in 5/8 patients, and contractures were seen in all 8 individuals, though only mild in 5. WGS of the proband identified a heterozygous c.378+1G>T variant in SMARCAD1 (same as in PMID: 21820097). Variant co-segregated with disease, maximal LOD score was 3.01. NON-SYNDROMIC ADERMATOGLYPHIA: PMID: 24909267 Nousbeck et al., 2014 3 families with isolated adermatoglyphia and heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) PMID: 21820097 Nousbeck et al., 2011 Report of a large Swiss kindred presenting with autosomal-dominant adermatoglyphia (9 affected, 7 unaffected). Linkage analysis gave a LOD score of 2.85. Sequencing detected a heterozygous variant in the skin-specific SMARCAD1 short isoform: c.378+1G>T. N.B.: PMID: 35592705 Xiong et al., 2022 - Basan syndrome family; ARTICLE RETRACTED SMARCAD1 is associated with AD Adermatoglyphia, MIM:136000; AD Basan syndrome, MIM:129200; AD Huriez syndrome, MIM:181600 (OMIM accessed 28th Aug 2026). |
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| Ichthyosis and erythrokeratoderma v4.1 | FLG |
Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma. |
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| Ichthyosis and erythrokeratoderma v4.1 | FLG |
Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma. |
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| Ichthyosis and erythrokeratoderma v4.1 | FLG |
Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma. |
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| Ichthyosis and erythrokeratoderma v4.1 | FLG |
Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). Heterozygous individuals also have an increased susceptibility to atopic dermatitis (PMID: 16550169 Palmer et al., 2006). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma. |
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| Ichthyosis and erythrokeratoderma v4.1 | FLG |
Ida Ertmanska changed review comment from: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma.; to: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and/or symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma. |
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| Ichthyosis and erythrokeratoderma v4.1 | FLG |
Ida Ertmanska commented on gene: FLG: There are at least 42 unrelated patients with variants in FLG with ichthyosis vulgaris and symmetrical acral keratoderma, which fits into the scope of this panel. Ichthyosis vulgaris is characterized clinically by xerosis, hyperkeratosis, excess scaling, keratosis pilaris, palmar and plantar hyperlinearity, and a strong association with atopic disorders. The penetrance of ichthyosis vulgaris is estimated at 83%–96%, with variable severity of symptoms; mild phenotype may escape diagnosis. Majority of affected individuals will experience symptoms before age 5. Importantly, the frequency and type of variants associated with disease varies between ancestry groups (PMID: 36751330 Jaffar et al., 2022). PMID:16444271 Smith et al., 2006: 7 unrelated families and 8 sporadic cases of Caucasian ancestry with Ichthyosis vulgaris who were heterozygous or homozygous for a stop codon c.1501C>T (p.Arg501Ter), or compound heterozygous for this variant and a frameshift variant c.2282_2285del (p.Ser761fs). Homozygous/compound heterozygous cases had a more severe phenotype. c.1501C>T p.(Arg501Ter) - European population frequency in gnomAD v4.1.0 = 0.02138, including 296 homozygotes. c.2282_2285del p.(Ser761fs) - European population freq in gnomad V.4.1.0 = 0.02330, including 386 homozygotes. PMID: 33807935 Fozia et al., 2021: Family D, Pakistani origin, consanguineous; phenotype: congenital erythroderma, ichthyosis vulgaris; method: WES; 3 affected members homozygous FLG: c.6109C>T; p. (Arg2037Ter) - gnomAD South Asian pop freq = 0.001164, 3 homozygotes. Symmetrical Acral Keratoderma (SAK) is a rare skin condition, more common in young Asian men, characterized by symmetrical, brownish-black, thickened skin patches (plaques) on the hands, feet, and wrists, with occasional involvement of elbows and knees (sparing the palms and soles). PMID:36716921 Liu et al., 2023: 33 of the 36 patients with SAK carried pathogenic variants in the FLG. Method: WES +Sanger validation. 20/36 of the individuals had ichthyosis vulgaris in addition to Symmetrical Acral Keratoderma. Functional studies: Knockdown of FLG in three-dimensional reconstructed human epidermis (RHE) showed hypogranulosis, a disturbed corneocyte intracellular matrix, impaired keratinocyte differentiation (PMID: 24940654 Pendaries et al., 2014). Newborn Flg(-/-) knockout mice exhibit dry scaly skin. The keratin patterns were lost, and the stratum corneum was fragile, leading to altered skin barrier integrity (PMID: 22409988 Kawasaki et al., 2012). Based on the available evidence, this gene should be rated Green for Ichthyosis and erythrokeratoderma. |
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| Ichthyosis and erythrokeratoderma v3.27 | DBR1 |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Zornitza Stark, the same variant was identified in four different families and haplotype analysis suggests this to be a founder variant.; to: Comment on list classification: As reviewed by Zornitza Stark, the same variant was identified in four different families and haplotype analysis suggests this to be a founder variant. There is functional data available. This gene can only be rated amber with the current evidence. The 'founder-effect' tag is added to this gene. |
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| Ichthyosis and erythrokeratoderma v3.27 | DBR1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, the same variant was identified in four different families and haplotype analysis suggests this to be a founder variant. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v3.3 | DBR1 |
Zornitza Stark gene: DBR1 was added gene: DBR1 was added to Ichthyosis and erythrokeratoderma. Sources: Literature Mode of inheritance for gene: DBR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DBR1 were set to 37656279 Phenotypes for gene: DBR1 were set to Ichthyosis (MONDO#0019269), DBR1-related Review for gene: DBR1 was set to AMBER Added comment: PMID: 37656279: - A homozygous missense as a founder recessive DBR1 variant in four consanguineous families. - Total of 7 affected children. WES done for one proband from each family. - Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life. - RNA and protein studies using fibroblasts derived from a patient are supportive of pathogenicity: RNA-seq, rt-qPCR and western blotting, showing marked reduction of DBR1 level and intronic RNA lariat accumulation in the patient sample. - Haplotype analysis revealed that the four families all share a haplotype extending at least 2.27 Mb around the c.200A>G p.(Tyr67Cys) DBR1 founder variant. - Authors proposed this is a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility, and highlighted the apparent lack of correlation with the degree of DBR1 deficiency. Sources: Literature |
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| Ichthyosis and erythrokeratoderma v1.55 | STS | Ivone Leong Phenotypes for gene: STS were changed from Ichthyosis, X-linked, 308100 to Ichthyosis, X-linked, OMIM:308100 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ichthyosis and erythrokeratoderma v1.3 | ASPRV1 |
Zornitza Stark gene: ASPRV1 was added gene: ASPRV1 was added to Ichthyosis and erythrokeratoderma. Sources: Literature Mode of inheritance for gene: ASPRV1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ASPRV1 were set to 32516568 Phenotypes for gene: ASPRV1 were set to palmoplantar keratoderma; lamellar ichthyosis Review for gene: ASPRV1 was set to GREEN gene: ASPRV1 was marked as current diagnostic Added comment: -3 heterozygous missense variants identified across 4 unrelated kindreds -mutant ASPRV1 expressed in human keratinocytes suggests impaired filaggrin processing Sources: Literature |
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| Ichthyosis and erythrokeratoderma v1.3 | PERP |
Zornitza Stark gene: PERP was added gene: PERP was added to Ichthyosis and erythrokeratoderma. Sources: Literature Mode of inheritance for gene: PERP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PERP were set to 31898316 Phenotypes for gene: PERP were set to Erythrokeratoderma, no OMIM # yet Review for gene: PERP was set to AMBER Added comment: One extended multiplex consanguineous family with Erythrokeratoderma (striking similarity to that observed in Perp −/− mice), and a novel homozygous variant (c.466G>A; p.Gly156Arg) in PERP that fully segregated with the phenotype. Functional analysis of patient‐ and control‐derived keratinocytes revealed a deleterious effect of the identified variant on the intracellular localization of PERP. A previous report showed that PERP mutation causes a dominant form of keratoderma but a single patient in that report with a homozygous variant in PERP suggests that recessive inheritance is also possible. Sources: Literature |
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| Ichthyosis and erythrokeratoderma v0.3 | STS |
Ellen McDonagh gene: STS was added gene: STS was added to Ichthyosis and erythrokeratoderma. Sources: Expert Review Green Mode of inheritance for gene: STS was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Phenotypes for gene: STS were set to Ichthyosis, X-linked, 308100 |
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