Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Hutterite Population

Stephanie E Wallace; Lora JH Bean

Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Hutterite Population

Wallace SE, Bean LJH.

Estimated reading time: 9 minutes

A founder variant is a pathogenic variant observed at high frequency in a specific population due to the presence of the variant in a single ancestor or small number of ancestors. The presence of a founder variant can affect the approach to molecular genetic testing. When one or more founder variants account for a large percentage of all pathogenic variants found in a population, testing for the founder variant(s) may be performed first.

The table below includes common founder variants – here defined as three or fewer variants that account for more than 50% of the pathogenic variants identified in a single gene in individuals of a specific ancestry – in individuals of Hutterite ancestry. Note: Pathogenic variants that are common worldwide due to a DNA sequence hot spot are not considered founder variants and thus are not included.

Table.

Genetic Disorders Associated with Founder Variants Common in the Hutterite Population

Revision History

1 December 2022 (sw) Revision: removed NPHP1 variants
7 May 2020 (sw) Initial posting

References

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Publication Details

Author Information and Affiliations

Stephanie E Wallace, MD

Senior Editor, GeneReviews

Clinical Professor, Pediatrics
University of Washington
Seattle, Washington

Email: ude.wu@2rotide

Lora JH Bean, PhD

Molecular Genetics Editor, GeneReviews

Senior Director, Laboratory Quality Assurance
Perkin-Elmer Genomics, Inc
Pittsburgh, Pennsylvania

Publication History

Initial Posting: May 7, 2020; Last Revision: December 1, 2022.

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NLM Citation

Wallace SE, Bean LJH. Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Hutterite Population. 2020 May 7 [Updated 2022 Dec 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

Table.

Genetic Disorders Associated with Founder Variants Common in the Hutterite Population

Gene	Disorder	MOI	DNA Nucleotide Change	Predicted Protein Change	Proportion of Pathogenic Variants in Gene	Carrier Frequency	Leut/Ethnicity (Specific Region)	Reference Sequences	References
ABCC8	Permanent neonatal diabetes mellitus	AR	See footnote 1.	–	~100% ²	Unknown	Schmeideleut	NM_000352.4	Triggs-Raine et al [2016]
ABCG8	Sitosterolemia	AR	c.320C>G	p.Ser107Ter	~100% ²	1/12 to 1/16	Schmeideleut	NM_022437.2 NP_071882.1	Chong et al [2012], Triggs-Raine et al [2016]
ALPL	Hypophosphatasia	AR	c.1001G>A	p.Gly334Asp	~100% ²	Unknown	Dariusleut	NM_000478.5 NP_000469.3	Triggs-Raine et al [2016]
AR	Androgen insensitivity syndrome	XL	c.2033T>C	p.Leu678Pro	~100% ²	Unknown	Schmiedeleut (Manitoba)	NM_000044.4 NP_000035.2	Belsham et al [1995]
BBS2	Bardet-Biedl syndrome	AR	c.472-2A>G	–	~100% ²	1/22 to 1/36	Dariusleut & Schmiedeleut	NM_031885.3	Chong et al [2012], Triggs-Raine et al [2016]
BCHE	Succinylcholine sensitivity (OMIM 617936)	AR	c.293A>G	p.Asp98Gly	~100% ²	1/21	Schmiedeleut	NM_000055.3 NP_000046.1	Zelinski et al [2007], Triggs-Raine et al [2016]
BCKDHB	Maple syrup urine disease	AR	c.595_596delAG	p.Pro200Ter	Unknown	Unknown	Hutterite	NM_183050.3 NP_898871.1	Mroch et al [2014]
CFTR	Cystic fibrosis	AR	c.1521_1523delCTT	p.Phe508del	31%	1/33 to 1/45	Dariusleut, Lehrerleut, & Schmiedeleut	NM_000492.3 NP_000483.3	Zielenski et al [1993], Chong et al [2012], Triggs-Raine et al [2016]
CFTR	Cystic fibrosis	AR	c.3302T>A	p.Met1101Lys	69%	1/14 to 1/16	Dariusleut, Lehrerleut, & Schmiedeleut	NM_000492.3 NP_000483.3
CPT1A	Carnitine palmitoyltransferase 1A deficiency	AR	c.2129G>A	p.Gly710Glu	~100% ²	1/15 to 1/16	Dariusleut & Schmiedeleut	NM_001876.3 NP_001867.2	Prasad et al [2001], Triggs-Raine et al [2016]
CSPP1	Joubert syndrome	AR	c.363_364delTA	p.His121GlnfsTer22	~100% ²	Unknown	Schmiedeleut	NM_024790.6 NP_079066.5	Shaheen et al [2014]
DNAJC19	Dilated cardiomyopathy with ataxia syndrome (OMIM 610198)	AR	c.130-1G>C	–	~100% ²	1/21 to 1/34	Dariusleut, Lehrerleut, & Schmiedeleut	NM_145261.3	Davey et al [2006], Chong et al [2012], Triggs-Raine et al [2016]
DPH1	Louks-Innes syndrome (OMIM 616901)	AR	c.17T>A	p.Met6Lys	~100% ²	1/32	Dariusleut	NM_001383.4 NP_001374.3	Loucks et al [2015], Triggs-Raine et al [2016]
DSC2	Arrhythmogenic right ventricular cardiomyopathy	AR	c.1660C>T	p.Gln554Ter	~100% ²	1/8 to 1/11	Dariusleut, Lehrerleut, & Schmiedeleut	NM_024422.4 NP_077740.1	Gerull et al [2013], Wong et al [2014], Triggs-Raine et al [2016]
EMG1	Bowen-Conradi syndrome (OMIM 211180)	AR	c.257A>G	p.Asp86Gly	~100% ²	1/10 to 1/21	Dariusleut, Lehrerleut, & Schmiedeleut	NM_006331.7 NP_006322.4	Armistead et al [2009], Triggs-Raine et al [2016]
FKRP	Limb-girdle muscular dystrophy type 2I (OMIM 607155)	AR	c.826C>A	p.Leu276Ile	~100% ²	1/7 to 1/9	Dariusleut, Lehrerleut, & Schmiedeleut	NM_024301.4 NP_077277.1	Frosk et al [2005], Chong et al [2012], Triggs-Raine et al [2016]
GJB2	GJB2-related autosomal recessive nonsyndromic hearing loss	AR	c.35delG	p.Gly12ValfsTer2	~100% ²	1/28 to 1/65	Dariusleut & Schmiedeleut	NM_004004.5 NP_003995.2	Chong et al [2012], Triggs-Raine et al [2016]
LEMD2	Juvenile-onset cataract and arrhythmic cardiomyopathy (OMIM 212500)	AR	c.38T>G	p.Leu13Arg	~100% ²	1/8	Schmiedeleut, Lehrerleut	NM_181336.3 NP_851853.1	Boone et al [2015], Abdelfatah et al [2019]
LMNA	Emery-Dreifuss muscular dystrophy	AR	c.1445G>A	p.Arg482Gln	~100% ²	1/69	Dariusleut & Lehrerleut (Alberta, Canada)	NM_170707.3 NP_733821.1	Wiltshire et al [2013]
MMUT	Methylmalonic acidemia	AR	c.1420C>T	p.Arg474Ter	~100% ²	1/63	Dariusleut	NM_000255.3 NP_000246.2	Triggs-Raine et al [2016]
MYO7A	Usher syndrome 1	AR	c.52C>T	p.Gln18Ter	~100% ²	Unknown	Dariusleut	NM_000260.3 NP_000251.3	Chong et al [2012]
NDUFS4	Leigh syndrome	AR	c.393dupA	p.Glu132ArgfsTer15	~100% ²	1/13	Dariusleut & Schmiedeleut	NM_002495.3 NP_002486.1	Triggs-Raine et al [2016]
PCDH15	Usher syndrome 1	AR	c.1088delT	p.Leu363TrpfsTer58	~100% ²	1/21 to 1/40	Schmeideleut ³	NM_033056.3 NP_149045.3	Alagramam et al [2001], Chong et al [2012]
PIBF1	Joubert syndrome	AR	c.1910A>C	p.Asp637Ala	~100% ²	Unknown	Schmiedeleut	NM_006346.3 NP_006337.2	Wheway et al [2015]
PROP1	PROP1-related combined pituitary hormone deficiency	AR	c.301_302delAG	p.Leu102CysfsTer8	~100% ²	Unknown	Hutterite	NM_006261.4 NP_006252.3	Wu et al [1998]
SLC39A8	Congenital disorder of glycosylation type IIn	AR	c.112G>C	p.Gly38Arg	~100% ²	1/59	Lehrerleut	NM_022154.5 NP_071437.3	Boycott et al [2015]
SLC39A8	Congenital disorder of glycosylation type IIn	AR	c.112G>C	p.Gly38Arg	~100% ²	1/26	Dariusleut	NM_022154.5 NP_071437.3	Boycott et al [2015]
SLC5A5	Thyroid dyshormonogenesis I (OMIM 274400)	AR	c.1183G>A	p.Gly395Arg	~100% ²	Unknown	Dariusleut, Lehrerleut, & Schmiedeleut	NM_000453.2 NP_000444.1	Kosugi et al [1999]
SMN1	Spinal muscular atrophy type III	AR	Del entire gene ⁴	–	<100% ⁵	1/8	Lehrerleut, Schmeideleut (South Dakota) ³	NM_000344.3 NP_000335.1	Chong et al [2011]
SQOR	Leigh syndrome	AR	c.637G>A	p.Glu213Lys	~100% ²	1/13	Lehrerleut	NM_021199.4 NP_067022.1	Friederich et al [2020]
TECR	Nonsyndromic mental retardation (OMIM 614020)	AR	c.545C>T	p.Pro182Leu	~100% ²	1/14 to 1/63	Schmeideleut	NM_138501.5 NP_612510.1	Chong et al [2012], Triggs-Raine et al [2016]
TH	Tyrosine hydroxylase deficiency	AR	c.1481C>T	p.Thr494Met	~100% ²	Unknown	Dariusleut	NM_199292.2 NP_954986.2	Boycott et al [2008]
THOC6	Beaulieu-Boycott-Innes syndrome	AR	c.136G>A	p.Gly46Arg	~100% ²	1/33	Dariusleut	NM_024339.4 NP_0778315.2	Beaulieu et al [2013]
THOC6	Beaulieu-Boycott-Innes syndrome	AR	c.136G>A	p.Gly46Arg	~100% ²	1/50	Lehrerleut	NM_024339.4 NP_0778315.2	Beaulieu et al [2013]
TMEM237	Joubert syndrome	AR	c.52C>T	p.Arg18Ter	~100% ²	1/12.5	Schmiedeleut	NM_001044385.2 NP_001037850.1	Chong et al [2012]
TMEM237	Joubert syndrome	AR	c.52C>T	p.Arg18Ter	~100% ²	1/17	Canadian Hutterites	NM_001044385.2 NP_001037850.1	Huang et al [2011]
TRAPPC11	Limb-girdle muscular dystrophy type 18 (OMIM 615356)	AR	c.1287+5G>A	p.Ala372_Ser429del	~100% ¹	1/8 to 1/14	Dariusleut & Schmeideleut	NM_021942.5	Bögershausen et al [2013], Triggs-Raine et al [2016]
TRIM32	Limb-girdle muscular dystrophy type 2H (OMIM 254110)	AR	c.1459G>A	p.Asp487Asn	~100% ²	1/6.5 to 1/31	Dariusleut, Lehrerleut, & Schmiedeleut	NM_012210.3 NP_036342.2	Chong et al [2012], Triggs-Raine et al [2016]
TYR	Oculocutaneous albinism type 1 (OMIM 203100, 606952)	AR	c.272G>A	p.Cys91Tyr	~100% ²	1/7 to 1/9	Dariusleut, Lehrerleut, & Schmiedeleut	NM_000372.4 NP_000363.1	Chong et al [2012], Triggs-Raine et al [2016]
VLDLR	VLDLR cerebellar hypoplasia	AR	Del entire gene Chr9:2479657-2678818del	–	~100% ²	1/15	Lehrerleut & Dariusleut	NC_000009.12 (GRCh18.p13)	Glass et al [2005]
ZMPSTE24	Restrictive dermopathy (OMIM 275210)	AR	c.1085dupT	p.Leu362PhefsTer19	~100% ²	1/15.5 to 1/21	Dariusleut, Lehrerleut, & Schmiedeleut	NM_005857.4 NP_005848.2	Loucks et al [2012], Chong et al [2012]

: Included if ≤3 pathogenic variants account for ≥50% of variants identified in a specific ethnic group; see also www.biochemgenetics.ca/plainpeople.

: AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked

1.: The c.823-7T>A variant is reported in Triggs-Raine et al [2016], attributed to a personal communication. No data regarding the pathogenicity of the variant are provided.

2.: To date, additional pathogenic variants in this gene have not been reported in individuals of Hutterite descent.

3.: Carrier frequency reported in Schmiedeleut population residing in United States [Chong et al 2011, Chong et al 2012, Gerull et al 2013]; carrier frequency in Lehrerleut and Dariusleut not reported to date

4.: Individuals of Hutterite ancestry with SMN1 founder deletion have 0 SMN1 and 2 SMN2 copies per chromosome.

5.: De novo pathogenic variants have been reported in Hutterite population [Chong et al 2011].